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Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets

Nature Reviews Cancer volume 24, pages 240–260 (2024)Cite this article

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Abstract

Protein lipidation describes a diverse class of post-translational modifications (PTMs) that is regulated by over 40 enzymes, targeting more than 1,000 substrates at over 3,000 sites. Lipidated proteins include more than 150 oncoproteins, including mediators of cancer initiation, progression and immunity, receptor kinases, transcription factors, G protein-coupled receptors and extracellular signalling proteins. Lipidation regulates the physical interactions of its protein substrates with cell membranes, regulating protein signalling and trafficking, and has a key role in metabolism and immunity. Targeting protein lipidation, therefore, offers a unique approach to modulate otherwise undruggable oncoproteins; however, the full spectrum of opportunities to target the dysregulation of these PTMs in cancer remains to be explored. This is attributable in part to the technological challenges of identifying the targets and the roles of protein lipidation. The early stage of drug discovery for many enzymes in the pathway contrasts with efforts for drugging similarly common PTMs such as phosphorylation and acetylation, which are routinely studied and targeted in relevant cancer contexts. Here, we review recent advances in identifying targetable protein lipidation pathways in cancer, the current state-of-the-art in drug discovery, and the status of ongoing clinical trials, which have the potential to deliver novel oncology therapeutics targeting protein lipidation.

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Fig. 1: Pathways regulating the major classes of protein lipidation.
Fig. 2: Oncoproteins regulated by protein prenylation.
Fig. 3: Protein myristoylation in cancer.
Fig. 4: Protein palmitoylation in cancer.
Fig. 5: Lipidated secreted proteins in cancer.

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References

  1. Chen, B., Sun, Y., Niu, J., Jarugumilli, G. K. & Wu, X. Protein lipidation in cell signaling and diseases: function, regulation, and therapeutic opportunities. Cell Chem. Biol. 25, 817–831 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jiang, H. et al. Protein lipidation: occurrence, mechanisms, biological functions, and enabling technologies. Chem. Rev. 118, 919–988 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Berndt, N., Hamilton, A. D. & Sebti, S. M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Meinnel, T., Dian, C. & Giglione, C. Myristoylation, an ancient protein modification mirroring eukaryogenesis and evolution. Trends Biochem. Sci. 45, 619–632 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Lanyon-Hogg, T., Faronato, M., Serwa, R. A. & Tate, E. W. Dynamic protein acylation: new substrates, mechanisms, and drug targets. Trends Biochem. Sci. 42, 566–581 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Tang, H. & Han, M. Fatty acids regulate germline sex determination through ACS-4-dependent myristoylation. Cell 169, 457–469.e13 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Lee, H. W. et al. A phase II trial of tipifarnib for patients with previously treated, metastatic urothelial carcinoma harboring HRAS mutations. Clin. Cancer Res. 26, 5113–5119 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Ho, A. L. et al. Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. J. Clin. Oncol. 39, 1856–1864 (2021). This study describes the clinical application of a farnesyltransferase inhibitor in HRAS-mutant cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mariscal, J. et al. Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles. J. Extracell. Vesicles 9, 1764192 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tohumeken, S. et al. Palmitoylated proteins on AML-derived extracellular vesicles promote myeloid-derived suppressor cell differentiation via TLR2/Akt/mTOR signaling. Cancer Res. 80, 3663–3676 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Clara, J. A., Monge, C., Yang, Y. & Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update. Nat. Rev. Clin. Oncol. 17, 204–232 (2020).

    Article  PubMed  Google Scholar 

  12. Kallemeijn, W. W. et al. Validation and invalidation of chemical probes for the human N-myristoyltransferases. Cell Chem. Biol. 26, 892–900.e4 (2019). The study has used an NMT inhibitor and demonstrated that widely used legacy tool compounds have primarily or exclusively off-target effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang, M. & Casey, P. J. Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17, 110–122 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Taylor, J. S., Reid, T. S., Terry, K. L., Casey, P. J. & Beese, L. S. Structure of mammalian protein geranylgeranyltransferase type-I. EMBO J. 22, 5963–5974 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Park, H. W., Boduluri, S. R., Moomaw, J. F., Casey, P. J. & Beese, L. S. Crystal structure of protein farnesyltransferase at 2.25 Ångstrom resolution. Science 275, 1800–1804 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Zverina, E. A., Lamphear, C. L., Wright, E. N. & Fierke, C. A. Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions. Curr. Opin. Chem. Biol. 16, 544–552 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Storck, E. M. et al. Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics. Nat. Chem. 11, 552–561 (2019). This study provides evidence for the extent of alternative prenylation, and tools for dissecting farnesyltransferase and geranylgeranyl transferase substrates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hampton, S. E., Dore, T. M. & Schmidt, W. K. Rce1: mechanism and inhibition. Crit. Rev. Biochem. Mol. Biol. 53, 157–174 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Diver, M. M., Pedi, L., Koide, A., Koide, S. & Long, S. B. Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT. Nature 553, 526–529 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Manolaridis, I. et al. Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1. Nature 504, 301–305 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Recchi, C. & Seabra, M. C. Novel functions for Rab GTPases in multiple aspects of tumour progression. Biochem. Soc. Trans. 40, 1398–1403 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jin, H. et al. Rab GTPases: central coordinators of membrane trafficking in cancer. Front. Cell Dev. Biol. 9, 648384 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Leung, K. F., Baron, R. & Seabra, M. C. Thematic review series: lipid posttranslational modifications. geranylgeranylation of Rab GTPases. J. Lipid Res. 47, 467–475 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Winter-Vann, A. M. & Casey, P. J. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat. Rev. Cancer 5, 405–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Kuchay, S. et al. GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase. Nat. Struct. Mol. Biol. 26, 628–636 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shirakawa, R. et al. A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus. EMBO J. 39, e104120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boudreau, D. M., Yu, O. & Johnson, J. Statin use and cancer risk: a comprehensive review. Expert Opin. Drug Saf. 9, 603–621 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jung, D. & Bachmann, H. S. Regulation of protein prenylation. Biomed. Pharmacother. 164, 114915 (2023).

    Article  CAS  PubMed  Google Scholar 

  29. Brandt, A. C., Koehn, O. J. & Williams, C. L. SmgGDS: an emerging master regulator of prenylation and trafficking by small GTPases in the Ras and Rho families. Front. Mol. Biosci. 8, 685135 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhou, M. et al. VPS35 binds farnesylated N-Ras in the cytosol to regulate N-Ras trafficking. J. Cell Biol. 214, 445–458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zimmermann, G. et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638–642 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Garcia-Mata, R., Boulter, E. & Burridge, K. The ‘invisible hand’: regulation of RHO GTPases by RHOGDIs. Nat. Rev. Mol. Cell Biol. 12, 493–504 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Losada de la Lastra, A., Hassan, S. & Tate, E. W. Deconvoluting the biology and druggability of protein lipidation using chemical proteomics. Curr. Opin. Chem. Biol. 60, 97–112 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao, H. et al. Roles of palmitoylation and the KIKK membrane-targeting motif in leukemogenesis by oncogenic KRAS4A. J. Hematol. Oncol. 8, 132 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cox, A. D., Der, C. J. & Philips, M. R. Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin. Cancer Res. 21, 1819–1827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Campbell, S. L. & Philips, M. R. Post-translational modification of RAS proteins. Curr. Opin. Struct. Biol. 71, 180–192 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lau, H. Y., Tang, J., Casey, P. J. & Wang, M. Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms. Oncogene 36, 3934–3942 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tang, J., Casey, P. J. & Wang, M. Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair. Life Sci. Alliance 4, e202101144 (2021).

  42. Chai, T. F., Manu, K. A., Casey, P. J. & Wang, M. Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal. Oncogene 39, 5373–5389 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Do, M. T., Chai, T. F., Casey, P. J. & Wang, M. Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin beta3 recycling, cell migration and cancer metastasis. Oncogene 36, 5757–5767 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Court, H., Ahearn, I. M., Amoyel, M., Bach, E. A. & Philips, M. R. Regulation of NOTCH signaling by RAB7 and RAB8 requires carboxyl methylation by ICMT. J. Cell Biol. 216, 4165–4182 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Karthikeyan, S., Casey, P. J. & Wang, M. RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation. Breast Cancer Res. 24, 72 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brandt, A. C. et al. Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy. Proc. Natl Acad. Sci. USA 117, 3627–3636 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zeissig, M. N., Ashwood, L. M., Kondrashova, O. & Sutherland, K. D. Next batter up! Targeting cancers with KRAS-G12D mutations. Trends Cancer 9, 955–967 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Kim, D. et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619, 160–166 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schulze, C. J. et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science 381, 794–799 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kallemeijn, W. W. et al. Proteome-wide analysis of protein lipidation using chemical probes: in-gel fluorescence visualization, identification and quantification of N-myristoylation, N- and S-acylation, O-cholesterylation, S-farnesylation and S-geranylgeranylation. Nat. Protoc. 16, 5083–5122 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Dhillon, S. Lonafarnib: first approval. Drugs 81, 283–289 (2021). This article describes the approval of lonafarnib, the first approved drug targeting a protein lipid transferase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gotlib, J. Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Curr. Hematol. Rep. 4, 77–84 (2005).

    CAS  PubMed  Google Scholar 

  55. Ben Yahia, H., Petit, F. M. & Saada-Bouzid, E. Targeting Harvey rat sarcoma viral oncogene homolog in head and neck cancer: how to move forward? Curr. Opin. Oncol. 35, 178–185 (2023).

    Article  PubMed  Google Scholar 

  56. Gatchalian, J., Kessler, L., Chan, S., Burrows, F. & Malik, S. Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models. Cancer Res. 83, abstr. 1071 (2023).

  57. Patel, H. V. et al. Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance. Cancer Res. 83, abstr. 1079 (2023).

  58. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04997902 (2021).

  59. Smith, A. E. et al. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity. Cancer Res. 83, 3252–3263 (2023). This study is a preclinical investigation of combination treatment with farnesyltransferase inhibitors, which led to a subsequent clinical trial.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Figarol, S. et al. Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC. Preprint at bioRxiv https://doi.org/10.1101/2022.04.01.486707 (2022).

  61. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03900442 (2019).

  62. Karasic, T. B., Chiorean, E. G., Sebti, S. M. & O’Dwyer, P. J. A phase I study of GGTI-2418 (geranylgeranyl transferase I inhibitor) in patients with advanced solid tumors. Target. Oncol. 14, 613–618 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lau, H. Y. et al. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol. Ther. 15, 1280–1291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sun, W. T. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia. Exp. Hematol. 44, 189–193.e2 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Papke, B. et al. Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat. Commun. 7, 11360 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Klein, C. H. et al. PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas. Int. J. Cancer 144, 767–776 (2019).

    Article  CAS  PubMed  Google Scholar 

  67. Leung, E. L. H. et al. Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. Cell Death Dis. 9, 216 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Cheng, J., Li, Y., Wang, X., Dong, G. & Sheng, C. Discovery of novel PDEδ degraders for the treatment of KRAS mutant colorectal cancer. J. Med. Chem. 63, 7892–7905 (2020).

    Article  CAS  PubMed  Google Scholar 

  69. Liao, D. et al. Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma. Nat. Cell Biol. 22, 868–881 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Van Acker, H. H., Anguille, S., Willemen, Y., Smits, E. L. & Van Tendeloo, V. F. Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials. Pharmacol. Ther. 158, 24–40 (2016).

    Article  PubMed  Google Scholar 

  71. Gralow, J. R. et al. Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307. J. Natl Cancer Inst. 112, 698–707 (2020).

    Article  PubMed  Google Scholar 

  72. Baranyi, M. et al. Next generation lipophilic bisphosphonate shows antitumor effect in colorectal cancer in vitro and in vivo. Pathol. Oncol. Res. 26, 1957–1969 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Xia, Y. et al. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci. Transl. Med. 6, 263ra161 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Longo, J., van Leeuwen, J. E., Elbaz, M., Branchard, E. & Penn, L. Z. Statins as anticancer agents in the era of precision medicine. Clin. Cancer Res. 26, 5791–5800 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Castrec, B. et al. Structural and genomic decoding of human and plant myristoylomes reveals a definitive recognition pattern. Nat. Chem. Biol. 14, 671–679 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Dian, C. et al. High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation. Nat. Commun. 11, 1132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Thinon, E. et al. Global profiling of co- and post-translationally N-myristoylated proteomes in human cells. Nat. Commun. 5, 4919 (2014). This study profiles the co-translationally and post-translationally myristoylated proteome in intact cells.

    Article  CAS  PubMed  Google Scholar 

  78. Rampoldi, F. et al. Immunosuppression and aberrant T cell development in the absence of N-myristoylation. J. Immunol. 195, 4228–4243 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576.e16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhu, X. G. et al. CHP1 regulates compartmentalized glycerolipid synthesis by activating GPAT4. Mol. Cell 74, 45–58.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wylie, A. A. et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 543, 733–737 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Wright, M. H., Heal, W. P., Mann, D. J. & Tate, E. W. Protein myristoylation in health and disease. J. Chem. Biol. 3, 19–35 (2010).

    Article  PubMed  Google Scholar 

  83. Wang, H., Xu, X., Wang, J. & Qiao, Y. The role of N-myristoyltransferase 1 in tumour development. Ann. Med. 55, 1422–1430 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019). This study identifies FSP1 as a ferroptosis-resistance factor and highlights the requirement of myristoylation for FSP1 activity, and potential for targeting FSP1 in cancer.

    Article  CAS  PubMed  Google Scholar 

  86. Beauchamp, E. et al. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat. Commun. 11, 5348 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Thinon, E., Morales-Sanfrutos, J., Mann, D. J. & Tate, E. W. N-Myristoyltransferase inhibition induces ER-stress, cell cycle arrest, and apoptosis in cancer cells. ACS Chem. Biol. 11, 2165–2176 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lueg, G. A. et al. N-Myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers. Preprint at bioRxiv https://doi.org/10.1101/2021.03.20.436222 (2021).

  89. Baertling, F. et al. NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect. Eur. J. Hum. Genet. 25, 1273–1277 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Colaco, A. & Jaattela, M. Ragulator — a multifaceted regulator of lysosomal signaling and trafficking. J. Cell Biol. 216, 3895–3898 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McHugh, D. et al. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells. Nat. Cell Biol. 25, 1804–1820 (2023). This study demonstrates the actionability of NMT as a target in senescence and reports very potent senolytic activity for several well-characterized NMTi.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nagar, B. et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112, 859–871 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Colicelli, J. ABL tyrosine kinases: evolution of function, regulation, and specificity. Sci. Signal. 3, re6 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Mackey, J. R. et al. N-Myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target. Breast Cancer Res. Treat. 186, 79–87 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liang, J. et al. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat. Commun. 6, 7926 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Schoepfer, J. et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J. Med. Chem. 61, 8120–8135 (2018). This study describes the first approved drug targeting a myristoylation event.

    Article  CAS  PubMed  Google Scholar 

  97. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02081378 (2014).

  98. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03106779 (2017).

  99. Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371–377 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, Q. et al. Metabolic reprogramming of ovarian cancer involves ACSL1-mediated metastasis stimulation through upregulated protein myristoylation. Oncogene 40, 97–111 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Kaiyrzhanov, R. et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain (2023).

  102. Kaiser, N. et al. Photoactivatable myristic acid probes for UNC119-cargo interactions. ChemBioChem 20, 134–139 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Garivet, G. et al. Small-molecule inhibition of the UNC-Src interaction impairs dynamic Src localization in cells. Cell Chem. Biol. 26, 842–851.e7 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Sun, Y. et al. N-Myristoyltransferase-1 deficiency blocks myristoylation of LAMTOR1 and inhibits bladder cancer progression. Cancer Lett. 529, 126–138 (2022).

    Article  CAS  PubMed  Google Scholar 

  105. Chen, Y. C. et al. N-Myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells. Sci. Rep. 10, 11952 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tameire, F. et al. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat. Cell Biol. 21, 889–899 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dong, H. et al. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nat. Immunol. 20, 865–878 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Timms, R. T. et al. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science 365, eaaw4912 (2019). This study describes the involvement of myristoylation in regulating protein degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yan, X. et al. Molecular basis for recognition of Gly/N-degrons by CRL2(ZYG11B) and CRL2(ZER1). Mol. Cell 81, 3262–3274.e3 (2021).

    Article  CAS  PubMed  Google Scholar 

  110. Honda, T. et al. Protective role for lipid modifications of Src-family kinases against chromosome missegregation. Sci. Rep. 6, 38751 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mousnier, A. et al. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. Nat. Chem. 10, 599–606 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dammert, M. A. et al. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat. Commun. 10, 3485 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Zirin, J. et al. Interspecies analysis of MYC targets identifies tRNA synthetases as mediators of growth and survival in MYC-overexpressing cells. Proc. Natl Acad. Sci. USA 116, 14614–14619 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sangha, R. et al. Novel, first-in-human, oral PCLX-001 treatment in a patient with relapsed diffuse large B-cell lymphoma. Curr. Oncol. 29, 1939–1946 (2022). This study provides a clinical report of NMT inhibitor treatment in a human.

    Article  PubMed  PubMed Central  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04836195 (2021).

  116. Bell, A. S. et al. Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. PLoS Negl. Trop. Dis. 6, e1625 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tovell, H. et al. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader. ACS Chem. Biol. 14, 2024–2034 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Carr, R. A. et al. N-Myristolytransferase (NMT) inhibitors as novel potent payloads for antibody drug conjugates. Cancer Res. 83, abstr. 2635 (2023).

    Article  Google Scholar 

  119. Zaballa, M. E. & van der Goot, F. G. The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics. Crit. Rev. Biochem. Mol. Biol. 53, 420–451 (2018).

    Article  PubMed  Google Scholar 

  120. Rana, M. S. et al. Fatty acyl recognition and transfer by an integral membrane S-acyltransferase. Science 359, eaao6326 (2018). This study describes the first structure of a ZDHHC enzyme.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lee, C. J. et al. Bivalent recognition of fatty acyl-CoA by a human integral membrane palmitoyltransferase. Proc. Natl Acad. Sci. USA 119, e2022050119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Verardi, R., Kim, J. S., Ghirlando, R. & Banerjee, A. Structural basis for substrate recognition by the ankyrin repeat domain of human DHHC17 palmitoyltransferase. Structure 25, 1337–1347.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Blanc, M., David, F. P. A. & van der Goot, F. G. SwissPalm 2: protein S-palmitoylation database. Methods Mol. Biol. 2009, 203–214 (2019). This paper describes the primary community-maintained database of palmitoyl-proteome datasets.

    Article  CAS  PubMed  Google Scholar 

  124. Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Noland, C. L. et al. Palmitoylation of TEAD transcription factors is required for their stability and function in Hippo pathway signaling. Structure 24, 179–186 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Chan, P. et al. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat. Chem. Biol. 12, 282–289 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chen, B. et al. Auto-fatty acylation of transcription factor RFX3 regulates ciliogenesis. Proc. Natl Acad. Sci. USA 115, E8403–E8412 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Eelen, G. et al. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature 561, 63–69 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Cory, A. O. et al. A palmitoyl transferase chemical genetic system to map ZDHHC-specific S-acylation. Preprint at bioRxiv https://doi.org/10.1101/2023.04.18.537386 (2023). This paper describes a chemical genetic system for multiple ZDHHC enzymes, enabling direct association of ZDHHCs with their cognate substrates in intact cells.

  130. Coleman, D. T., Gray, A. L., Kridel, S. J. & Cardelli, J. A. Palmitoylation regulates the intracellular trafficking and stability of c-Met. Oncotarget 7, 32664–32677 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Dubois, F., Leroy, C., Simon, V., Benistant, C. & Roche, S. YES oncogenic activity is specified by its SH4 domain and regulates RAS/MAPK signaling in colon carcinoma cells. Am. J. Cancer Res. 5, 1972–1987 (2015).

    PubMed  PubMed Central  Google Scholar 

  132. Sancier, F. et al. Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells. PLoS ONE 6, e17237 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Runkle, K. B. et al. Inhibition of DHHC20-mediated EGFR palmitoylation creates a dependence on EGFR signaling. Mol. Cell 62, 385–396 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kharbanda, A. et al. Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis. Sci. Signal. 13, eaax2364 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bollu, L. R. et al. Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation. Oncotarget 6, 34992–35003 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Ali, A. et al. Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. EMBO Mol. Med. 10, e8313 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Chen, S. et al. Palmitoylation-dependent activation of MC1R prevents melanomagenesis. Nature 549, 399–403 (2017). This study demonstrates a key role for palmitoylation in melanomagenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Perez, C. J. et al. Increased susceptibility to skin carcinogenesis associated with a spontaneous mouse mutation in the palmitoyl transferase Zdhhc13 gene. J. Invest. Dermatol. 135, 3133–3143 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, S. et al. Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads. Nat. Commun. 10, 877 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Ahearn, I., Zhou, M. & Philips, M. R. Posttranslational modifications of RAS proteins. Cold Spring Harb. Perspect. Med. 8, a031484 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cuiffo, B. & Ren, R. Palmitoylation of oncogenic NRAS is essential for leukemogenesis. Blood 115, 3598–3605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zambetti, N. A. et al. Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice. Blood 135, 1772–1782 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Liu, P. et al. Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras. Leukemia 30, 1225–1228 (2016).

    Article  CAS  PubMed  Google Scholar 

  144. Remsberg, J. R. et al. ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth. Nat. Chem. Biol. 17, 856–864 (2021). This article describes a small molecule inhibitor of ABHD17 and investigates the effect of depalmitoylation on NRAS function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Amendola, C. R. et al. KRAS4A directly regulates hexokinase 1. Nature 576, 482–486 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tsai, F. D. et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc. Natl Acad. Sci. USA 112, 779–784 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sun, Y. et al. ZDHHC2-mediated AGK palmitoylation activates AKT–mTOR signaling to reduce sunitinib sensitivity in renal cell carcinoma. Cancer Res. 83, 2034–2051 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sun, Y. et al. S-Palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway. Cell Rep. 40, 111194 (2022).

    Article  CAS  PubMed  Google Scholar 

  149. Sharma, C., Yang, W., Steen, H., Freeman, M. R. & Hemler, M. E. Antioxidant functions of DHHC3 suppress anti-cancer drug activities. Cell. Mol. Life Sci. 78, 2341–2353 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Frohlich, M., Dejanovic, B., Kashkar, H., Schwarz, G. & Nussberger, S. S-Palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis. Cell Death Dis. 5, e1057 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Feig, C., Tchikov, V., Schutze, S. & Peter, M. E. Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling. EMBO J. 26, 221–231 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Chakrabandhu, K. et al. Palmitoylation is required for efficient Fas cell death signaling. EMBO J. 26, 209–220 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Berg, V. et al. miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL. Blood 125, 2948–2957 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Chen, Y. A. et al. WW domain-containing proteins YAP and TAZ in the Hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis. Front. Oncol. 9, 60 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Holden, J. K. et al. Small molecule dysregulation of TEAD lipidation induces a dominant-negative inhibition of Hippo pathway signaling. Cell Rep. 31, 107809 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Kaneda, A. et al. The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma. Am. J. Cancer Res. 10, 4399–4415 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Tang, T. T. et al. Small molecule inhibitors of TEAD auto-palmitoylation selectively inhibit proliferation and tumor growth of NF2-deficient mesothelioma. Mol. Cancer Ther. 20, 986–998 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Hagenbeek, T. J. et al. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance. Nat. Cancer 4, 812–828 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05228015 (2022).

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04665206 (2021).

  161. Tolcher, A. W. et al. A phase 1, first-in-human study of IK-930, an oral TEAD inhibitor targeting the Hippo pathway in subjects with advanced solid tumors. J. Clin. Oncol. 40, TPS3168 (2022). A first-in-human study of an inhibitor of TEAD S-acylation.

    Article  Google Scholar 

  162. Yap, T. A. et al. First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of Yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations. Cancer Res. 83, abstr. CT006 (2023).

    Article  Google Scholar 

  163. Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhang, M. et al. A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. Nature 586, 434–439 (2020). This study demonstrates a key role for ZDHHC7 and APT2 in STAT3 activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Hernandez, L. M. et al. Palmitoylation-dependent control of JAK1 kinase signaling governs responses to neuropoietic cytokines and survival in DRG neurons. J. Biol. Chem. 299, 104965 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Collura, K. M. et al. The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway. J. Biol. Chem. 295, 15427–15437 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ma, Y. et al. DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3. Glia 70, 379–392 (2022).

    Article  CAS  PubMed  Google Scholar 

  168. Yao, H. et al. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat. Biomed. Eng. 3, 306–317 (2019). This study demonstrates a key role for ZDHHC3 in the palmitoylation of PD-L1 and cancer immunity.

    Article  CAS  PubMed  Google Scholar 

  169. Yang, Y. et al. Palmitoylation stabilizes PD-L1 to promote breast tumor growth. Cell Res. 29, 83–86 (2019).

    Article  PubMed  Google Scholar 

  170. Yao, H. et al. A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions. RSC Chem. Biol. 2, 192–205 (2021).

    Article  CAS  PubMed  Google Scholar 

  171. Borden, E. C. Interferons alpha and beta in cancer: therapeutic opportunities from new insights. Nat. Rev. Drug Discov. 18, 219–234 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Du, W. et al. Loss of optineurin drives cancer immune evasion via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation. Cancer Discov. 11, 1826–1843 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Claudinon, J. et al. Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha. J. Biol. Chem. 284, 24328–24340 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mukai, K. et al. Activation of STING requires palmitoylation at the Golgi. Nat. Commun. 7, 11932 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).

    Article  CAS  PubMed  Google Scholar 

  176. Liu, Y. et al. ZDHHC11 modulates innate immune response to DNA virus by mediating MITA-IRF3 association. Cell Mol. Immunol. 15, 907–916 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Zhou, Q. et al. The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Cell Host Microbe 16, 450–461 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Goran, T. et al. Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis. Preprint at bioRxiv https://doi.org/10.1101/2023.02.08.527637 (2023).

  179. Morphy, R. Selectively nonselective kinase inhibition: striking the right balance. J. Med. Chem. 53, 1413–1437 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Puthenveetil, R. et al. Orthogonal enzyme–substrate design strategy for discovery of human protein palmitoyltransferase substrates. J. Am. Chem. Soc. 145, 22287–22292 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Won, S. J. et al. Molecular mechanism for isoform-selective inhibition of acyl protein thioesterases 1 and 2 (APT1 and APT2). ACS Chem. Biol. 11, 3374–3382 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lan, T., Delalande, C. & Dickinson, B. C. Inhibitors of DHHC family proteins. Curr. Opin. Chem. Biol. 65, 118–125 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Ergun, S. L., Fernandez, D., Weiss, T. M. & Li, L. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. Cell 178, 290–301.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  184. Davda, D. et al. Profiling targets of the irreversible palmitoylation inhibitor 2-bromopalmitate. ACS Chem. Biol. 8, 1912–1917 (2013). This study profiles the targets of 2-bromopalmitate and identifies promiscuous reactivity, highlighting the need for caution when using it as an inhibitor of palmitoylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Salaun, C. et al. Development of a novel high-throughput screen for the identification of new inhibitors of protein S-acylation. J. Biol. Chem. 298, 102469 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Zhang, Z. et al. DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis. Nat. Commun. 12, 5872 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Flanagan, D. J., Woodcock, S. A., Phillips, C., Eagle, C. & Sansom, O. J. Targeting ligand-dependent Wnt pathway dysregulation in gastrointestinal cancers through Porcupine inhibition. Pharmacol. Ther. 238, 108179 (2022).

    Article  CAS  PubMed  Google Scholar 

  188. Chamoun, Z. et al. Skinny Hedgehog, an acyltransferase required for palmitoylation and activity of the Hedgehog signal. Science 293, 2080–2084 (2001).

    Article  CAS  PubMed  Google Scholar 

  189. Bordeau, B. M., Ciulla, D. A. & Callahan, B. P. Hedgehog proteins consume steroidal CYP17A1 antagonists: potential therapeutic significance in advanced prostate cancer. ChemMedChem 11, 1983–1986 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Masumoto, N. et al. Membrane bound O-acyltransferases and their inhibitors. Biochem. Soc. Trans. 43, 246–252 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. Chaudhry, P., Singh, M., Triche, T. J., Guzman, M. & Merchant, A. A. GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML. Blood 129, 3465–3475 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Tesanovic, S., Krenn, P. W. & Aberger, F. Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia — from bench to bedside. Front. Cell Dev. Biol. 10, 944760 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Steele, N. G. et al. Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer. Clin. Cancer Res. 27, 2023–2037 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Regan, J. L. et al. Non-canonical Hedgehog signaling is a positive regulator of the WNT pathway and is required for the survival of colon cancer stem cells. Cell Rep. 21, 2813–2828 (2017).

    Article  CAS  PubMed  Google Scholar 

  195. Quatannens, D. et al. Targeting Hedgehog signaling in pancreatic ductal adenocarcinoma. Pharmacol. Ther. 236, 108107 (2022).

    Article  CAS  PubMed  Google Scholar 

  196. Liang, R. et al. Acyltransferase skinny Hedgehog regulates TGFβ-dependent fibroblast activation in SSc. Ann. Rheum. Dis. 78, 1269–1273 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Flanagan, D. J. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Doan, H. Q. et al. Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma. Oncotarget 12, 2089–2100 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Bayle, E. D. et al. Carboxylesterase Notum is a druggable target to modulate Wnt signaling. J. Med. Chem. 64, 4289–4311 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Rodon, J. et al. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br. J. Cancer 125, 28–37 (2021). This study provides a clinical report of a first-in-class Porcupine inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Neiheisel, A., Kaur, M., Ma, N., Havard, P. & Shenoy, A. K. Wnt pathway modulators in cancer therapeutics: an update on completed and ongoing clinical trials. Int. J. Cancer 150, 727–740 (2022).

    Article  CAS  PubMed  Google Scholar 

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01351103 (2011).

  203. Phillips, C. et al. The Wnt pathway inhibitor RXC004 blocks tumor growth and reverses immune evasion in Wnt ligand-dependent cancer models. Cancer Res. Commun. 2, 914–928 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04907851 (2021).

  205. Natalie, C. et al. Phase 1 study of the Porcupine (PORCN) inhibitor RXC004 in combination with the PD-1 inhibitor nivolumab in patients with advanced solid tumors. J. Immunother. Cancer 10, A752 (2022).

    Google Scholar 

  206. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03447470 (2019).

  207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04907539 (2021).

  208. Liu, Y. et al. Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Nature 607, 816–822 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Huels, D. J. et al. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells. Nat. Commun. 9, 1132 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Zhao, Y., Jolly, S., Benvegnu, S., Jones, E. Y. & Fish, P. V. Small-molecule inhibitors of carboxylesterase Notum. Future Med. Chem. 13, 1001–1015 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Lanyon-Hogg, T. et al. Photochemical probe identification of a small-molecule inhibitor binding site in Hedgehog acyltransferase (HHAT)*. Angew. Chem. Int. Ed. Engl. 60, 13542–13547 (2021). This study describes the most potent HHAT inhibitor identified to date.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Jiang, Y., Benz, T. L. & Long, S. B. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Science 372, 1215–1219 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Coupland, C. E. et al. Structure, mechanism, and inhibition of Hedgehog acyltransferase. Mol. Cell 81, 5025–5038.e10 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Konitsiotis, A. D. et al. Topological analysis of Hedgehog acyltransferase, a multipalmitoylated transmembrane protein. J. Biol. Chem. 290, 3293–3307 (2015).

    Article  CAS  PubMed  Google Scholar 

  215. Matevossian, A. & Resh, M. D. Membrane topology of Hedgehog acyltransferase. J. Biol. Chem. 290, 2235–2243 (2015).

    Article  CAS  PubMed  Google Scholar 

  216. Asciolla, J. J. & Resh, M. D. Hedgehog acyltransferase promotes uptake of palmitoyl-CoA across the endoplasmic reticulum membrane. Cell Rep. 29, 4608–4619.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Petrova, E., Rios-Esteves, J., Ouerfelli, O., Glickman, J. F. & Resh, M. D. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling. Nat. Chem. Biol. 9, 247–249 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Rodgers, U. R. et al. Characterization of Hedgehog acyltransferase inhibitors identifies a small molecule probe for Hedgehog signaling by cancer cells. ACS Chem. Biol. 11, 3256–3262 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Matevossian, A. & Resh, M. D. Hedgehog acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells. Mol. Cancer 14, 72 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Lanyon-Hogg, T. et al. Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP): a universal assay for lipid transferase and hydrolase enzymes. Chem. Sci. 10, 8995–9000 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Jiang, H. et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Zhang, X., Spiegelman, N. A., Nelson, O. D., Jing, H. & Lin, H. SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation. eLife 6, e25158 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Jing, H. et al. SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a. eLife 6, e32436 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Penteado, A. B., Hassanie, H., Gomes, R. A., Silva Emery, F. D. & Goulart Trossini, G. H. Human sirtuin 2 inhibitors, their mechanisms and binding modes. Future Med. Chem. 15, 291–311 (2023).

    Article  CAS  PubMed  Google Scholar 

  225. Haston, S. et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell 41, 1242–1260.e6 (2023).

    Article  CAS  PubMed  Google Scholar 

  226. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03719690 (2018).

  227. Wang, M. et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem. 283, 18678–18684 (2008).

    Article  CAS  PubMed  Google Scholar 

  228. Wang, M. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene 29, 4959–4970 (2010).

    Article  CAS  PubMed  Google Scholar 

  229. Teh, J. T. et al. Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene 34, 3296–3304 (2015).

    Article  CAS  PubMed  Google Scholar 

  230. Manu, K. A. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces cell-cycle arrest and apoptosis through p21 and p21-regulated BNIP3 induction in pancreatic cancer. Mol. Cancer Ther. 16, 914–923 (2017).

    Article  CAS  PubMed  Google Scholar 

  231. Hinz, S., Jung, D., Hauert, D. & Bachmann, H. S. Molecular and pharmacological characterization of the interaction between human geranylgeranyltransferase type I and Ras-related protein Rap1B. Int. J. Mol. Sci. 22, 2501 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Alizadeh, J. et al. Mevalonate cascade inhibition by simvastatin induces the intrinsic apoptosis pathway via depletion of isoprenoids in tumor cells. Sci. Rep. 7, 44841 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Adibekian, A. et al. Characterization of a selective, reversible inhibitor of lysophospholipase 1 (LYPLA1). Probe Reports from the NIH Molecular Libraries Program [Internet] https://www.ncbi.nlm.nih.gov/books/NBK189924/ (updated 13 Jan 2014).

  234. Adibekian, A. et al. Characterization of a selective, veversible inhibitor of lysophospholipase 2 (LYPLA2). Probe Reports from the NIH Molecular Libraries Program [Internet] https://www.ncbi.nlm.nih.gov/books/NBK189927/ (updated 18 Sep 2014).

  235. Zheng, B. et al. 2-Bromopalmitate analogues as activity-based probes to explore palmitoyl acyltransferases. J. Am. Chem. Soc. 135, 7082–7085 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Hagemann, A. et al. Analyzing the postulated inhibitory effect of manumycin A on farnesyltransferase. Front. Chem. 10, 967947 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Dekker, F. J. et al. Small-molecule inhibition of APT1 affects Ras localization and signaling. Nat. Chem. Biol. 6, 449–456 (2010).

    Article  CAS  PubMed  Google Scholar 

  238. Rusch, M. et al. Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras-signaling modulators palmostatin B and M. Angew. Chem. Int. Ed. 50, 9838–9842 (2011).

    Article  CAS  Google Scholar 

  239. Lin, D. T. S. & Conibear, E. ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. eLife 4, e11306 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Sterling, J., Baker, J. R., McCluskey, A. & Munoz, L. Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research. Nat. Commun. 14, 3228 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Mader, M. M. et al. Which small molecule? Selecting chemical probes for use in cancer research and target validation. Cancer Discov. 13, 2150–2165 (2023).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

H.L. thanks the National Institutes of Health for support (R01DK107451), and M.W. thanks the Ministry of Health Singapore (MOH-000944-00). E.W.T. thanks Cancer Research UK and the Engineering and Physical Sciences Research Council for the support (DRCNPG-Nov21\100001, C29637/A20183, C29637/A27506, C24523/A27435). The authors thank T. Burden for his help in reviewing the manuscript.

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Authors and Affiliations

  1. Department of Chemistry, Imperial College London, London, UK

    Edward W. Tate, Lior Soday & Ana Losada de la Lastra

  2. Francis Crick Institute, London, UK

    Edward W. Tate

  3. Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

    Mei Wang

  4. Department of Biochemistry, National University of Singapore, Singapore, Singapore

    Mei Wang

  5. Howard Hughes Medical Institute, Cornell University, Ithaca, NY, USA

    Hening Lin

  6. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Hening Lin

  7. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA

    Hening Lin

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  1. Edward W. Tate
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  3. Ana Losada de la Lastra
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  4. Mei Wang
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  5. Hening Lin
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All authors made a substantial contribution to the discussion of the content of the Review and contributed to writing, researching data for the article and reviewing the manuscript before submission.

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Correspondence to Edward W. Tate.

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Competing interests

H.L. is a founder and consultant for Sedec Therapeutics. E.W.T. is a founding director and shareholder of Myricx Pharma Ltd. and a named inventor on patents covering NMT inhibitors (WO2017001812A1, PCT/GB2019/053613), is an adviser of and holds share options in Sasmara Therapeutics, and receives current or recent funding from Myricx Pharma Ltd, Pfizer Ltd, Kura Oncology, AstraZeneca, Merck & Co. and GSK. The remaining authors declare no competing interests.

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Glossary

Acyl protein thioesterases

Enzymes of the hydrolase family responsible for the removal of S-acyl modifications on proteins.

Bisphosphonate drugs

Drugs targeting the biosynthesis of the prenyl pyrophosphate substrates of prenyltransferases.

Chemotypes

A chemical structure motif or primary substructure that is common to a group of compounds.

Deacylation

Also known as depalmitoylation. In the context of S-acylation, this process involves hydrolysis of the thioester linkage to return the free thiol cysteine side chain, catalysed by acyl protein thioesterases.

Endomembranes

Collective term encompassing all intracellular membranes, and excluding the plasma membrane, for example, the membranes of the ER, Golgi, vesicular trafficking system, nuclear envelope and so on.

Farnesylation

S-Prenylation with a 15-carbon (farnesyl) lipid.

Ferroptosis

A form of programmed cell death driven by iron-dependent phospholipid peroxidation.

Geranylgeranylation

S-Prenylation with a 20-carbon (geranylgeranyl) lipid.

Glycine N-degron

A signal defined by the presence of an N-terminal glycine in a protein, which directs Cullin 2 RING E3 ligase-dependent ubiquitination, leading to degradation.

Isoprenoid biosynthesis

The metabolic cascade giving rise to isoprenyl metabolites, including precursors of cholesterol and the prenyl pyrophosphate substrates of the prenyltransferases.

KIKK motif

A polybasic amino acid motif in the hypervariable region of KRAS4A that, together with S-acylation, mediates its plasma-membrane targeting.

Lipidation

The covalent attachment of a lipid (long-chain fatty acid) post-translational modification to a protein via an amino acid side chain, the N terminus or the C terminus.

N-Myristoylation

The transfer of a 14-carbon saturated long-chain fatty acid (C14:0) from myristoyl-coenzyme A to the N terminus of a protein via a stable amide linkage, catalysed by N-myristoyltransferase.

O-Palmitoleoylation

The modification of an alcohol side chain, for example, of a serine residue, with an unsaturated C16:1 lipid. Added to secreted WNT ligands by PORCN, in which it has an important role in trafficking and signalling.

Palmitoylation

In the context of protein lipidation, modification with a palmitoyl (C16:0) chain, for example, of a thiol on a cysteine side chain via a thioester linkage, or of an amine at the N terminus of a protein, via an amide linkage. Commonly, but formally incorrectly, used to describe the general process of multiple lengths of long-chain S-acylation at cysteine.

Philadelphia translocation

Translocation of ABL1 gene from chromosome 9 to BCR gene on chromosome 22, generating oncogenic BCR–ABL1 fusion protein.

Prenyltransferases

Enzymes that transfer a prenyl group (farnesyl or geranylgeranyl) from a prenyl pyrophosphate to the thiol of a cysteine residue in a substrate protein, typically at the C terminus.

S-Acylation

The transfer of a long-chain fatty acid (typically C16:0, C18:0 or C20:0) from an acyl-CoA to a cysteine side chain via a thioester, catalysed by a member of the ZDHHC family of S-acyltransferases; frequently grouped under the term S-palmitoylation as the most common S-acylation is C16:0.

Splice-switching oligonucleotide

(SSO). Synthetic modified oligonucleotides design to alter splicing through base pairing to pre-spliced mRNA.

S-Prenylation

Transfer of a polyprenyl lipid from a prenyl pyrophosphate to a cysteine side chain via a stable thioether linkage, catalysed by a prenyltransferase.

Statins

A class of drugs inhibiting isoprenoid biosynthesis upstream of cholesterol biosynthesis, widely used to reduce cholesterol in people at risk of heart disease.

Zinc finger DHHC domain-containing (ZDHHC) family

A family of zinc finger S-acyltransferases containing an Asp–Cys–Cys–His motif.

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Tate, E.W., Soday, L., de la Lastra, A.L. et al. Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets. Nat Rev Cancer 24, 240–260 (2024). https://doi.org/10.1038/s41568-024-00666-x

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