Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of tumor metabolism by post translational modifications on metabolic enzymes

Cancer Gene Therapy volume 30, pages 548–558 (2023)Cite this article

Subjects

Abstract

Metabolic reprogramming is a hallmark of cancer development, progression, and metastasis. Several metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, lipid metabolism, and glutamine catabolism are frequently altered to support cancer growth. Importantly, the activity of the rate-limiting metabolic enzymes in these pathways are specifically modulated in cancer cells. This is achieved by transcriptional, translational, and post translational regulations that enhance the expression, activity, stability, and substrate sensitivity of the rate-limiting enzymes. These mechanisms allow the enzymes to retain increased activity supporting the metabolic needs of rapidly growing tumors, sustain their survival in the hostile tumor microenvironments and in the metastatic lesions. In this review, we primarily focused on the post translational modifications of the rate-limiting enzymes in the glucose and glutamine metabolism, TCA cycle, and fatty acid metabolism promoting tumor progression and metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Post-translational modifications on glycolytic enzymes modulate glucose metabolism and regulate flow of metabolic flux towards several biosynthetic pathways.
Fig. 2: Critical post-translational modifications of metabolic enzymes regulating mitochondrial TCA cycle, glutamine metabolism, and de novo fatty acid biosynthesis.

Similar content being viewed by others

References

  1. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.

    Article  CAS  PubMed  Google Scholar 

  2. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thomas F, Roche B, Ujvari B. Intrinsic versus extrinsic cancer risks: the debate continues. Trends Cancer 2016;2:68–9.

    Article  PubMed  Google Scholar 

  4. Blundon MA, Dasgupta S. Metabolic dysregulation controls endocrine therapy-resistant cancer recurrence and metastasis. Endocrinology 2019;160:1811–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mazziotta C, Lanzillotti C, Gafà R, Touzé A, Durand MA, Martini F, et al. The role of histone post-translational modifications in merkel cell carcinoma. Front Oncol. 2022;12:832047.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 2011;71:2892–900.

    Article  CAS  PubMed  Google Scholar 

  7. Kinnaird A, Zhao S, Wellen KE, Michelakis ED. Metabolic control of epigenetics in cancer. Nat Rev Cancer. 2016;16:694–707.

    Article  CAS  PubMed  Google Scholar 

  8. Campbell SL, Wellen KE. Metabolic signaling to the nucleus in cancer. Mol Cell. 2018;71:398–408.

    Article  CAS  PubMed  Google Scholar 

  9. Jiang G, Li C, Lu M, Lu K, Li H. Protein lysine crotonylation: past, present, perspective. Cell Death Dis. 2021;12:703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Trefely S, Lovell CD, Snyder NW, Wellen KE. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol Metab. 2020;38:100941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sabari BR, Zhang D, Allis CD, Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol. 2017;18:90–101.

    Article  CAS  PubMed  Google Scholar 

  12. Hirschey MD, Zhao Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol Cell Proteom. 2015;14:2308–15.

    Article  CAS  Google Scholar 

  13. Sreedhar A, Wiese EK, Hitosugi T. Enzymatic and metabolic regulation of lysine succinylation. Genes Dis. 2020;7:166–71.

    Article  CAS  PubMed  Google Scholar 

  14. Deng L, Meng T, Chen L, Wei W, Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther. 2020;5:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nat Rev Nephrol. 2019;15:346–66.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol cell Biol. 2005;6:150–66.

    Article  CAS  PubMed  Google Scholar 

  17. Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep. 2018;19:e46666.

  18. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    Article  CAS  PubMed  Google Scholar 

  19. Cori CF, Cori GT. The carbohydrate metabolism of tumors II. Changes in the sugar, lactic acid, and CO2-combining power of blood passing through a tumor. J Biol Chem. 1925;65:397–405.

    Article  CAS  Google Scholar 

  20. Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2:881–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2:e1600200.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee EE, Ma J, Sacharidou A, Mi W, Salato VK, Nguyen N, et al. A protein kinase C phosphorylation motif in GLUT1 affects glucose transport and is mutated in GLUT1 deficiency syndrome. Mol Cell. 2015;58:845–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Siska PJ, Rathmell JC. PKCs sweeten cell metabolism by phosphorylation of Glut1. Mol Cell. 2015;58:711–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang Z, Li X, Yang F, Chen C, Liu P, Ren Y, et al. DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis. Nat Commun. 2021;12:5872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Du K, Murakami S, Sun Y, Kilpatrick CL, Luscher B. DHHC7 palmitoylates glucose transporter 4 (Glut4) and regulates Glut4 membrane translocation. J Biol Chem. 2017;292:2979–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jeyaraj S, Boehmer C, Lang F, Palmada M. Role of SGK1 kinase in regulating glucose transport via glucose transporter GLUT4. Biochem Biophys Res Commun. 2007;356:629–35.

    Article  CAS  PubMed  Google Scholar 

  28. Sun K, Tang S, Hou Y, Xi L, Chen Y, Yin J, et al. Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling. EBioMedicine 2019;41:370–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Andrisse S, Patel GD, Chen JE, Webber AM, Spears LD, Koehler RM, et al. ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle. PLoS ONE. 2013;8:e66027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang J, Wang S, Jiang B, Huang L, Ji Z, Li X, et al. c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis. Nat Commun. 2017;8:13732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang T, Ren C, Qiao P, Han X, Wang L, Lv S, et al. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Oncogene 2018;37:5997–6009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li H, Lu S, Chen Y, Zheng L, Chen L, Ding H, et al. AKT2 phosphorylation of hexokinase 2 at T473 promotes tumorigenesis and metastasis in colon cancer cells via NF-κB, HIF1α, MMP2, and MMP9 upregulation. Cell Signal. 2019;58:99–110.

    Article  CAS  PubMed  Google Scholar 

  33. Li TY, Sun Y, Liang Y, Liu Q, Shi Y, Zhang CS, et al. ULK1/2 constitute a bifurcate node controlling glucose metabolic fluxes in addition to autophagy. Mol Cell. 2016;62:359–70.

    Article  CAS  PubMed  Google Scholar 

  34. Mathupala SP, Ko YH, Pedersen PL, Hexokinase II. cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 2006;25:4777–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hitosugi T, Chen J. Post-translational modifications and the Warburg effect. Oncogene 2014;33:4279–85.

    Article  CAS  PubMed  Google Scholar 

  36. Lee HJ, Li CF, Ruan D, He J, Montal ED, Lorenz S, et al. Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion. Nat Commun. 2019;10:2625.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Roberts DJ, Tan-Sah VP, Smith JM, Miyamoto S. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem. 2013;288:23798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shangguan X, He J, Ma Z, Zhang W, Ji Y, Shen K, et al. SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis. Nat Commun 2021;12:1812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012;337:975–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pilkis SJ, Claus TH, Kurland IJ, Lange AJ. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme. Annu Rev Biochem. 1995;64:799–835.

    Article  CAS  PubMed  Google Scholar 

  41. Tornheim K, Lowenstein JM. Control of phosphofructokinase from rat skeletal muscle. Effects of fructose diphosphate, AMP, ATP, and citrate. J Biol Chem. 1976;251:7322–8.

    Article  CAS  PubMed  Google Scholar 

  42. Furuya E, Uyeda K. An activation factor of liver phosphofructokinase. Proc Natl Acad Sci USA. 1980;77:5861–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 2018;556:249–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dasgupta S, Lonard DM, O’Malley BW. Nuclear receptor coactivators: master regulators of human health and disease. Annu Rev Med. 2014;65:279–92.

    Article  CAS  PubMed  Google Scholar 

  45. Dasgupta S, O’Malley BW. Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology. J Mol Endocrinol. 2014;53:R47–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li T, Liu M, Feng X, Wang Z, Das I, Xu Y, et al. Glyceraldehyde-3-phosphate dehydrogenase is activated by lysine 254 acetylation in response to glucose signal. J Biol Chem. 2014;289:3775–85.

    Article  CAS  PubMed  Google Scholar 

  47. Ci S, Xia W, Liang W, Qin L, Zhang Y, Dianov GL, et al. Src-mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage. FASEB J. 2020;34:10443–61.

    Article  CAS  PubMed  Google Scholar 

  48. Harada N, Yasunaga R, Higashimura Y, Yamaji R, Fujimoto K, Moss J, et al. Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells. J Biol Chem. 2007;282:22651–61.

    Article  CAS  PubMed  Google Scholar 

  49. Demarse NA, Ponnusamy S, Spicer EK, Apohan E, Baatz JE, Ogretmen B, et al. Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. J Mol Biol. 2009;394:789–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chang C, Su H, Zhang D, Wang Y, Shen Q, Liu B, et al. AMPK-dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for autophagy upon glucose starvation. Mol cell. 2015;60:930–40.

    Article  CAS  PubMed  Google Scholar 

  51. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005;7:665–74.

    Article  CAS  PubMed  Google Scholar 

  52. Nakamura T, Tu S, Akhtar MW, Sunico CR, Okamoto S, Lipton SA. Aberrant protein s-nitrosylation in neurodegenerative diseases. Neuron 2013;78:596–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N, et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008;10:866–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Galván-Peña S, Carroll RG, Newman C, Hinchy EC, Palsson-McDermott E, Robinson EK, et al. Malonylation of GAPDH is an inflammatory signal in macrophages. Nat Commun. 2019;10:338.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chaneton B, Gottlieb E. PGAMgnam style: a glycolytic switch controls biosynthesis. Cancer Cell. 2012;22:565–6.

    Article  CAS  PubMed  Google Scholar 

  56. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012;22:585–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem. 2012;287:3850–8.

    Article  CAS  PubMed  Google Scholar 

  58. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, et al. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun. 2013;4:1790.

    Article  PubMed  Google Scholar 

  59. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.

    Article  PubMed Central  Google Scholar 

  60. Israelsen WJ, Vander, Heiden MG. Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol. 2015;43:43–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nandi S, Razzaghi M, Srivastava D, Dey M. Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation. J Biol Chem. 2020;295:17425–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009;2:ra73.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell. 2011;42:719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell. 2013;52:340–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang Y, Liu J, Jin X, Zhang D, Li D, Hao F, et al. O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect. Proc Natl Acad Sci USA. 2017;114:13732–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14:1295–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2012;150:685–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell. 2014;53:75–87.

    Article  CAS  PubMed  Google Scholar 

  69. Lincet H, Icard P. How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene 2015;34:3751–9.

    Article  CAS  PubMed  Google Scholar 

  70. Lu Z, Hunter T. Metabolic kinases moonlighting as protein kinases. Trends Biochemical Sci. 2018;43:301–10.

    Article  CAS  Google Scholar 

  71. Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Investig. 2013;123:3685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jin L, Chun J, Pan C, Alesi GN, Li D, Magliocca KR, et al. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 2017;36:3797–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fan J, Hitosugi T, Chung TW, Xie J, Ge Q, Gu TL, et al. Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD( + ) redox homeostasis in cancer cells. Mol Cell Biol. 2011;31:4938–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell. 2013;23:464–76.

    Article  CAS  PubMed  Google Scholar 

  75. Li X, Zhang C, Zhao T, Su Z, Li M, Hu J, et al. Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer. J Exp Clin Cancer Res: CR. 2020;39:172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cheng A, Zhang P, Wang B, Yang D, Duan X, Jiang Y, et al. Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect. Nat Commun. 2019;10:5566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Warburg O. Über den Stoffwechsel der Carcinomzelle. Naturwissenschaften 1924;12:1131.

    Article  CAS  Google Scholar 

  78. Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell 2016;166:555–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 2007;104:19345–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell. 2014;53:534–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Saunier E, Benelli C, Bortoli S. The pyruvate dehydrogenase complex in cancer: an old metabolic gatekeeper regulated by new pathways and pharmacological agents. Int J Cancer. 2016;138:809–17.

    Article  CAS  PubMed  Google Scholar 

  82. Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell. 2011;44:864–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.

    Article  PubMed  Google Scholar 

  84. Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 2014;158:84–97.

    Article  CAS  PubMed  Google Scholar 

  85. Kankotia S, Stacpoole PW. Dichloroacetate and cancer: new home for an orphan drug? Biochim Biophys Acta. 2014;1846:617–29.

    CAS  PubMed  Google Scholar 

  86. Małecki J, Jakobsson ME, Ho AYY, Moen A, Rustan AC, Falnes P. Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation. J Biol Chem. 2017;292:17950–62.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE. Human METTL12 is a mitochondrial methyltransferase that modifies citrate synthase. FEBS Lett. 2017;591:1641–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bulteau AL, Ikeda-Saito M, Szweda LI. Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry 2003;42:14846–55.

    Article  CAS  PubMed  Google Scholar 

  89. Ternette N, Yang M, Laroyia M, Kitagawa M, O’Flaherty L, Wolhulter K, et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep. 2013;3:689–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fernandes J, Weddle A, Kinter CS, Humphries KM, Mather T, Szweda LI, et al. Lysine acetylation activates mitochondrial aconitase in the heart. Biochemistry 2015;54:4008–18.

    Article  CAS  PubMed  Google Scholar 

  91. Dasgupta S, Putluri N, Long W, Zhang B, Wang J, Kaushik AK, et al. Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis. J Clin Investig. 2015;125:1174–88.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Sawant Dessai A, Dominguez MP, Chen UI, Hasper J, Prechtl C, Yu C, et al. Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive prostate cancer to the bone. Cancer Res. 2021;81:50–63.

    PubMed  Google Scholar 

  93. Hooftman A, O’Neill LAJ. The immunomodulatory potential of the metabolite itaconate. Trends Immunol. 2019;40:687–98.

    Article  CAS  PubMed  Google Scholar 

  94. O’Neill LAJ, Artyomov MN. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol. 2019;19:273–81.

    Article  PubMed  Google Scholar 

  95. Weiss JM, Davies LC, Karwan M, Ileva L, Ozaki MK, Cheng RY, et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J Clin Invest. 2018;128:3794–805.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Smolková K, Špačková J, Gotvaldová K, Dvořák A, Křenková A, Hubálek M, et al. SIRT3 and GCN5L regulation of NADP+- and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2. Sci Rep. 2020;10:8677.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Yu W, Dittenhafer-Reed KE, Denu JM. SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J Biol Chem. 2012;287:14078–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zou X, Zhu Y, Park SH, Liu G, O’Brien J, Jiang H, et al. SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth. Cancer Res. 2017;77:3990–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ye D, Guan KL, Xiong Y. Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer 2018;4:151–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tort F, Ferrer-Cortès X, Thió M, Navarro-Sastre A, Matalonga L, Quintana E, et al. Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes. Hum Mol Genet. 2014;23:1907–15.

    Article  CAS  PubMed  Google Scholar 

  101. Bailey PSJ, Ortmann BM, Martinelli AW, Houghton JW, Costa ASH, Burr SP, et al. ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex. Nat Commun. 2020;11:4046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sun RC, Denko NC. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 2014;19:285–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 2017;552:273–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bezawork-Geleta A, Rohlena J, Dong L, Pacak K, Neuzil J. Mitochondrial complex II: at the crossroads. Trends Biochemical Sci. 2017;42:312–25.

    Article  CAS  Google Scholar 

  105. Barletta JA, Hornick JL. Succinate dehydrogenase-deficient tumors: diagnostic advances and clinical implications. Adv Anat Pathol. 2012;19:193–203.

    Article  CAS  PubMed  Google Scholar 

  106. Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 2011;1807:1432–43.

    Article  CAS  PubMed  Google Scholar 

  107. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–42.

    Article  CAS  PubMed  Google Scholar 

  108. Smith EH, Janknecht R, Maher LJ 3rd. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum Mol Genet. 2007;16:3136–48.

    Article  CAS  PubMed  Google Scholar 

  109. Cervera AM, Bayley JP, Devilee P, McCreath KJ. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer. 2009;8:89.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Laukka T, Mariani CJ, Ihantola T, Cao JZ, Hokkanen J, Kaelin WG Jr, et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J Biol Chem. 2016;291:4256–65.

    Article  CAS  PubMed  Google Scholar 

  111. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Acín-Pérez R, Carrascoso I, Baixauli F, Roche-Molina M, Latorre-Pellicer A, Fernández-Silva P, et al. ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use. Cell Metab. 2014;19:1020–33.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010;49:304–11.

    Article  CAS  PubMed  Google Scholar 

  114. Finley LW, Haas W, Desquiret-Dumas V, Wallace DC, Procaccio V, Gygi SP, et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One. 2011;6:e23295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chinopoulos C. The mystery of extramitochondrial proteins lysine succinylation. Int J Mol Sci. 2021;22:6085.

  116. Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab. 2013;18:920–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Adam J, Yang M, Bauerschmidt C, Kitagawa M, O’Flaherty L, Maheswaran P, et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 2013;3:1440–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Investig. 2013;123:3652–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–10.

    Article  CAS  PubMed  Google Scholar 

  120. Wang T, Yu Q, Li J, Hu B, Zhao Q, Ma C, et al. O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency. Nat Cell Biol. 2017;19:833–43.

    Article  PubMed  Google Scholar 

  121. Jiang Y, Qian X, Shen J, Wang Y, Li X, Liu R, et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol. 2015;17:1158–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen T, Wang T, Liang W, Zhao Q, Yu Q, Ma CM, et al. PAK4 phosphorylates fumarase and blocks TGFβ-induced cell growth arrest in lung cancer cells. Cancer Res. 2019;79:1383–97.

    Article  CAS  PubMed  Google Scholar 

  123. Yogev O, Yogev O, Singer E, Shaulian E, Goldberg M, Fox TD, et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 2010;8:e1000328.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Develop Biol. 2012;23:362–9.

    Article  CAS  Google Scholar 

  125. Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene 2016;35:3619–25.

    Article  CAS  PubMed  Google Scholar 

  126. Yang L, Venneti S, Nagrath D. Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng. 2017;19:163–94.

    Article  CAS  PubMed  Google Scholar 

  127. DeBerardinis RJ. Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010;29:313–24.

    Article  CAS  PubMed  Google Scholar 

  128. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Reynolds MR, Lane AN, Robertson B, Kemp S, Liu Y, Hill BG, et al. Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 2014;33:556–66.

    Article  CAS  PubMed  Google Scholar 

  130. Console L, Scalise M, Tarmakova Z, Coe IR, Indiveri C. N-linked glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane. Biochim Biophys Acta. 2015;1853:1636–45.

    Article  CAS  PubMed  Google Scholar 

  131. Jeon YJ, Khelifa S, Ratnikov B, Scott DA, Feng Y, Parisi F, et al. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell. 2015;27:354–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 2016;35:3201–8.

    Article  PubMed  Google Scholar 

  133. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020;31:267–83. e12

    Article  CAS  PubMed  Google Scholar 

  134. Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, et al. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proc Natl Acad Sci USA. 2012;109:1092–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ascenção CFR, Nagampalli RSK, Islam Z, Pinheiro MP, Menezes Dos Reis L, Pauletti BA, et al. N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration. Biochimie 2018;154:69–76.

    Article  PubMed  Google Scholar 

  136. Han T, Zhan W, Gan M, Liu F, Yu B, Chin YE, et al. Phosphorylation of glutaminase by PKCε is essential for its enzymatic activity and critically contributes to tumorigenesis. Cell Res. 2018;28:655–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ferreira AP, Cassago A, Gonçalves Kde A, Dias MM, Adamoski D, Ascenção CF, et al. Active glutaminase C self-assembles into a supratetrameric oligomer that can be disrupted by an allosteric inhibitor. J Biol Chem. 2013;288:28009–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Greene KS, Lukey MJ, Wang X, Blank B, Druso JE, Lin MJ, et al. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc Natl Acad Sci USA. 2019;116:26625–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA. 2010;107:7455–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA. 2010;107:7461–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kuo TC, Chen CK, Hua KT, Yu P, Lee WJ, Chen MW, et al. Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells. Cancer Lett. 2016;383:282–94.

    Article  CAS  PubMed  Google Scholar 

  142. López de la Oliva AR, Campos-Sandoval JA, Gómez-García MC, Cardona C, Martín-Rufián M, Sialana FJ, et al. Nuclear translocation of glutaminase GLS2 in human cancer cells associates with proliferation arrest and differentiation. Sci Rep. 2020;10:2259.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Wang L, Zhu L, Wu K, Chen Y, Lee DY, Gucek M, et al. Mitochondrial general control of amino acid synthesis 5 like 1 regulates glutaminolysis, mammalian target of rapamycin complex 1 activity, and murine liver regeneration. Hepatology. 2020;71:643–57.

    Article  CAS  PubMed  Google Scholar 

  144. Bunik V, Artiukhov A, Aleshin V, Mkrtchyan G. Multiple forms of glutamate dehydrogenase in animals: structural determinants and physiological implications. Biology. 2016;5:53.

  145. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA. 2011;108:19611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jiang L, Shestov AA, Swain P, Yang C, Parker SJ, Wang QA, et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 2016;532:255–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2011;481:380–4.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2011;481:385–8.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Choi MM, Huh JW, Yang SJ, Cho EH, Choi SY, Cho SW. Identification of ADP-ribosylation site in human glutamate dehydrogenase isozymes. FEBS Lett. 2005;579:4125–30.

    Article  CAS  PubMed  Google Scholar 

  150. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126:941–54.

    Article  CAS  PubMed  Google Scholar 

  151. Herrero-Yraola A, Bakhit SM, Franke P, Weise C, Schweiger M, Jorcke D, et al. Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in mitochondria. EMBO J. 2001;20:2404–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell. 2015;27:257–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Liu G, Zhu J, Yu M, Cai C, Zhou Y, Yu M, et al. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J Transl Med. 2015;13:144.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Zhang J, Wang G, Mao Q, Li S, Xiong W, Lin Y, et al. Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma. Oncotarget. 2016;295:799–800.

  155. Spinelli JB, Yoon H, Ringel AE, Jeanfavre S, Clish CB, Haigis MC. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science. 2017;358:941–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 2009;69:7986–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Wang X, Liu R, Qu X, Yu H, Chu H, Zhang Y, et al. α-Ketoglutarate-activated NF-κB signaling promotes compensatory glucose uptake and brain tumor development. Mol Cell. 2019;76:148–62. e7

    Article  CAS  PubMed  Google Scholar 

  158. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013;496:101–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer. 2020;122:4–22.

    Article  CAS  PubMed  Google Scholar 

  160. Munir R, Lisec J, Swinnen JV, Zaidi N. Lipid metabolism in cancer cells under metabolic stress. Br J Cancer. 2019;120:1090–8.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732–49.

    Article  PubMed  Google Scholar 

  163. Dasgupta S, Zhang B, Louet JF, O’Malley BW. Steroid receptor coactivator-2 mediates oncogenic reprogramming of cancer cell metabolism. Cancer Res. 2012;72:5153.

    Article  Google Scholar 

  164. Icard P, Poulain L, Lincet H. Understanding the central role of citrate in the metabolism of cancer cells. Biochim Biophys Acta. 2012;1825:111–6.

    CAS  PubMed  Google Scholar 

  165. Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008;68:8547–54.

    Article  CAS  PubMed  Google Scholar 

  166. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014;20:306–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Potapova IA, El-Maghrabi MR, Doronin SV, Benjamin WB. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 2000;39:1169–79.

    Article  CAS  PubMed  Google Scholar 

  168. Martinez Calejman C, Trefely S, Entwisle SW, Luciano A, Jung SM, Hsiao W, et al. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat Commun. 2020;11:575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. The. J Biol Chem. 2002;277:33895–900.

    Article  CAS  PubMed  Google Scholar 

  170. Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013;51:506–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhang C, Liu J, Huang G, Zhao Y, Yue X, Wu H, et al. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 2016;30:1956–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sivanand S, Rhoades S, Jiang Q, Lee JV, Benci J, Zhang J, et al. Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Mol Cell. 2017;67:252–65. e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM. Regulation of acetyl-CoA carboxylase. Biochem Soc Trans. 2006;34:223–7.

    Article  CAS  PubMed  Google Scholar 

  174. Hunkeler M, Hagmann A, Stuttfeld E, Chami M, Guri Y, Stahlberg H, et al. Structural basis for regulation of human acetyl-CoA carboxylase. Nature 2018;558:470–4.

    Article  CAS  PubMed  Google Scholar 

  175. Izumi A, Hiraguchi H, Kodaka M, Ikeuchi E, Narita J, Kobayashi R, et al. MIG12 is involved in the LXR activation-mediated induction of the polymerization of mammalian acetyl-CoA carboxylase. Biochem Biophys Res Commun. 2021;567:138–42.

    Article  CAS  PubMed  Google Scholar 

  176. Kim CW, Moon YA, Park SW, Cheng D, Kwon HJ, Horton JD. Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc Natl Acad Sci USA. 2010;107:9626–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. German NJ, Yoon H, Yusuf RZ, Murphy JP, Finley LW, Laurent G, et al. PHD3 loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2. Mol cell. 2016;63:1006–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ha J, Daniel S, Broyles SS, Kim KH. Critical phosphorylation sites for acetyl-CoA carboxylase activity. J Biol Chem. 1994;269:22162–8.

    Article  CAS  PubMed  Google Scholar 

  179. Ray H, Moreau K, Dizin E, Callebaut I, Venezia ND. ACCA phosphopeptide recognition by the BRCT repeats of BRCA1. J Mol Biol. 2006;359:973–82.

    Article  CAS  PubMed  Google Scholar 

  180. Magnard C, Bachelier R, Vincent A, Jaquinod M, Kieffer S, Lenoir GM, et al. BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT domains. Oncogene 2002;21:6729–39.

    Article  CAS  PubMed  Google Scholar 

  181. Ray H, Suau F, Vincent A, Dalla Venezia N. Cell cycle regulation of the BRCA1/acetyl-CoA-carboxylase complex. Biochem Biophys Res Commun. 2009;378:615–9.

    Article  CAS  PubMed  Google Scholar 

  182. Shen Y, Tong L. Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1. Biochemistry 2008;47:5767–73.

    Article  CAS  PubMed  Google Scholar 

  183. Rios Garcia M, Steinbauer B, Srivastava K, Singhal M, Mattijssen F, Maida A, et al. Acetyl-CoA carboxylase 1-dependent protein acetylation controls breast cancer metastasis and recurrence. Cell Metab. 2017;26:842–55.

    Article  CAS  PubMed  Google Scholar 

  184. Choi MS, Jung JY, Kim HJ, Ham MR, Lee TR, Shin DW. S-nitrosylation of fatty acid synthase regulates its activity through dimerization. J Lipid Res. 2016;57:607–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Baldini SF, Wavelet C, Hainault I, Guinez C, Lefebvre T. The nutrient-dependent O-GlcNAc modification controls the expression of liver fatty acid synthase. J Mol Biol. 2016;428:3295–304.

    Article  CAS  PubMed  Google Scholar 

  186. Jin Q, Yuan LX, Boulbes D, Baek JM, Wang YN, Gomez-Cabello D, et al. Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells. Breast Cancer Res. 2010;12:R96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, et al. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell. 2004;5:253–61.

    Article  CAS  PubMed  Google Scholar 

  188. Dasgupta S, Srinidhi S, Vishwanatha JK. Oncogenic activation in prostate cancer progression and metastasis: molecular insights and future challenges. J Carcinogenesis. 2012;11:4.

    Article  Google Scholar 

  189. Zhang J, Song F, Zhao X, Jiang H, Wu X, Wang B, et al. EGFR modulates monounsaturated fatty acid synthesis through phosphorylation of SCD1 in lung cancer. Mol Cancer. 2017;16:127.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Tesfay L, Paul BT, Konstorum A, Deng Z, Cox AO, Lee J, et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 2019;79:5355–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Wang C, Shi M, Ji J, Cai Q, Zhao Q, Jiang J, et al. Stearoyl-CoA desaturase 1 (SCD1) facilitates the growth and anti-ferroptosis of gastric cancer cells and predicts poor prognosis of gastric cancer. Aging. 2020;12:15374–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Yi J, Zhu J, Wu J, Thompson CB, Jiang X. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci USA. 2020;117:31189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z, et al. HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep. 2020;33:108487.

    Article  CAS  PubMed  Google Scholar 

  194. Schlaepfer IR, Joshi M. CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. Endocrinology. 2020;161:bqz046.

  195. Casals N, Zammit V, Herrero L, Fadó R, Rodríguez-Rodríguez R, Serra D. Carnitine palmitoyltransferase 1C: from cognition to cancer. Prog Lipid Res. 2016;61:134–48.

    Article  CAS  PubMed  Google Scholar 

  196. Distler AM, Kerner J, Hoppel CL. Post-translational modifications of rat liver mitochondrial outer membrane proteins identified by mass spectrometry. Biochim Biophys Acta. 2007;1774:628–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Eaton S, Fukumoto K, Stefanutti G, Spitz L, Zammit VA, Pierro A. Myocardial carnitine palmitoyltransferase I as a target for oxidative modification in inflammation and sepsis. Biochem Soc Trans. 2003;31:1133–6.

    Article  CAS  PubMed  Google Scholar 

  198. Kerner J, Distler AM, Minkler P, Parland W, Peterman SM, Hoppel CL. Phosphorylation of rat liver mitochondrial carnitine palmitoyltransferase-I: effect on the kinetic properties of the enzyme. J Biol Chem. 2004;279:41104–13.

    Article  CAS  PubMed  Google Scholar 

  199. Kurmi K, Hitosugi S, Wiese EK, Boakye-Agyeman F, Gonsalves WI, Lou Z, et al. Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity. Cell Rep. 2018;22:1365–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study is supported by funds from NIH (DP2CA260421 and R01CA252092), and Roswell Park Alliance Foundation to S.D.

Author information

Authors and Affiliations

  1. Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Abhisha Sawant Dessai, Poonam Kalhotra, Aaron T. Novickis & Subhamoy Dasgupta

Authors
  1. Abhisha Sawant Dessai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Poonam Kalhotra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aaron T. Novickis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Subhamoy Dasgupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ASD, PK, ATN, and SD conceived the ideas, researched the data for the manuscript, discussed the manuscript content, and wrote the manuscript. All authors reviewed and edited the article before submission.

Corresponding author

Correspondence to Subhamoy Dasgupta.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sawant Dessai, A., Kalhotra, P., Novickis, A.T. et al. Regulation of tumor metabolism by post translational modifications on metabolic enzymes. Cancer Gene Ther 30, 548–558 (2023). https://doi.org/10.1038/s41417-022-00521-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00521-x

This article is cited by

Search

Advanced search

Quick links