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.

  • Article
  • Published:

TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity

Oncogene volume 42, pages 35–48 (2023)Cite this article

Subjects

Abstract

The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy.

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: TNFα promotes IDH1 K115 acetylation and IDH1 degradation.
Fig. 2: TNFα inhibits SIRT1-mediated deacetylation of the IDH1 K115 site.
Fig. 3: TNFα promotes the ubiquitination and degradation of IDH1.
Fig. 4: CRC cells with TNFα-induced hyperacetylated IDH1 are sensitive to 5FU.
Fig. 5: TNFα-dependent IDH1 hyperacetylation was accompanied by an increase in ROS production and a decrease in NADPH/NADP expression.
Fig. 6: IDH1 hyperacetylation was closely associated with TNFα infiltration and sensitivity to 5FU treatment.
Fig. 7: Correlation between IDH1 acetylation and TNFα in human CRC tissues.
Fig. 8: Schematic illustration of TNFα-induced IDH1 acetylation alters CRC cell responsiveness to chemotherapeutics.

Similar content being viewed by others

References

  1. Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17:111–30.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  Google Scholar 

  3. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:22.

    Article  CAS  Google Scholar 

  4. Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future. Pharm Ther. 2020;206:107447.

    Article  CAS  Google Scholar 

  5. Kryeziu K, Bruun J, Guren TK, Sveen A, Lothe RA. Combination therapies with HSP90 inhibitors against colorectal cancer. Biochim Biophys Acta Rev Cancer. 2019;1871:240–7.

    Article  CAS  Google Scholar 

  6. Lizardo DY, Kuang C, Hao S, Yu J, Huang Y, Zhang L. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: from bench to bedside. Biochim Biophys Acta Rev Cancer. 2020;1874:188447.

    Article  CAS  Google Scholar 

  7. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol (Dordr). 2020;43:1–18.

    Article  CAS  Google Scholar 

  8. De Simone V, Franzè E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene. 2015;34:3493–503.

    Article  Google Scholar 

  9. Shen J, Xiao Z, Zhao Q, Li M, Wu X, Zhang L, et al. Anti-cancer therapy with TNFα and IFNγ: a comprehensive review. Cell Prolif. 2018;51:e12441.

    Article  Google Scholar 

  10. Lee JH, Kang MJ, Han HY, Lee MG, Jeong SI, Ryu BK, et al. Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis. Clin Cancer Res. 2011;17:7551–62.

    Article  CAS  Google Scholar 

  11. Lu L, Li ZJ, Li LF, Wu WK, Shen J, Zhang L, et al. Vascular-targeted TNFα improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer. J Control Release. 2015;210:134–46.

    Article  CAS  Google Scholar 

  12. Fluckiger A, Dumont A, Derangère V, Rébé C, de Rosny C, Causse S, et al. Inhibition of colon cancer growth by docosahexaenoic acid involves autocrine production of TNFα. Oncogene. 2016;35:4611–22.

    Article  CAS  Google Scholar 

  13. Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015;15:362–74.

    Article  CAS  Google Scholar 

  14. Walther W, Kobelt D, Bauer L, Aumann J, Stein U. Chemosensitization by diverging modulation by short-term and long-term TNF-α action on ABCB1 expression and NF-κB signaling in colon cancer. Int J Oncol. 2015;47:2276–85.

    Article  CAS  Google Scholar 

  15. Calvert AE, Chalastanis A, Wu Y, Hurley LA, Kouri FM, Bi Y, et al. Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep. 2017;19:1858–73.

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. Chen L, Zhang Z, Hoshino A, Zheng HD, Morley M, Arany Z, et al. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat Metab. 2019;1:404–15.

    Article  CAS  Google Scholar 

  18. Kong MJ, Han SJ, Kim JI, Park JW, Park KM. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase deficiency increases cisplatin-induced oxidative damage in the kidney tubule cells. Cell Death Dis. 2018;9:488.

    Article  Google Scholar 

  19. Yang H, Xie S, Liang B, Tang Q, Liu H, Wang D, et al. Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil. J Cancer. 2021;12:4862–72.

    Article  CAS  Google Scholar 

  20. Weeks J, Strom AI, Widjaja V, Alexander S, Pucher DK, Sohl CD. Evaluating mechanisms of IDH1 regulation through site-specific acetylation mimics. Biomolecules. 2021;11:740.

    Article  CAS  Google Scholar 

  21. Wang B, Ye Y, Yang X, Liu B, Wang Z, Chen S, et al. SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. EMBO Rep. 2020;21:e48183.

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. Rardin MJ, Newman JC, Held JM, Cusack MP, Sorensen DJ, Li B, et al. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc Natl Acad Sci USA. 2013;110:6601–6.

    Article  CAS  Google Scholar 

  24. Carafa V, Nebbioso A, Cuomo F, Rotili D, Cobellis G, Bontempo P, et al. RIP1–HAT1–SIRT complex identification and targeting in treatment and prevention of cancer. Clin Cancer Res. 2018;24:2886–900.

    Article  CAS  Google Scholar 

  25. Zhang Z, Lin G, Yan Y, Li X, Hu Y, Wang J, et al. Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene. 2018;37:3456–70.

    Article  CAS  Google Scholar 

  26. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012;150:165–78.

    Article  CAS  Google Scholar 

  27. Lasry A, Zinger A, Ben-Neriah Y. Inflammatory networks underlying colorectal cancer. Nat Immunol. 2016;17:230–40.

    Article  CAS  Google Scholar 

  28. Oliver Metzig M, Fuchs D, Tagscherer KE, Gröne HJ, Schirmacher P, Roth W. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene. 2016;35:3399–409.

    Article  CAS  Google Scholar 

  29. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009;9:361–71.

    Article  CAS  Google Scholar 

  30. Narayanan S, Cai CY, Assaraf YG, Guo HQ, Cui Q, Wei L, et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat. 2020;48:100663.

    Article  Google Scholar 

  31. denDekker AD, Davis FM, Joshi AD, Wolf SJ, Allen R, Lipinski J, et al. TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF. JCI Insight. 2020;5:e132306.

    Article  Google Scholar 

  32. Moon DO, Kim MO, Kang SH, Choi YH, Kim GY. Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. Cancer Lett. 2009;274:132–42.

    Article  CAS  Google Scholar 

  33. Meng F, Yang M, Chen Y, Chen W, Wang W. miR-34a induces immunosuppression in colorectal carcinoma through modulating a SIRT1/NF-κB/B7-H3/TNF-α axis. Cancer Immunol Immunother. 2021;70:2247–59.

    Article  CAS  Google Scholar 

  34. Hou J, Wang T, Xie Q, Deng W, Yang JY, Zhang SQ, et al. N-Myc-interacting protein (NMI) negatively regulates epithelial-mesenchymal transition by inhibiting the acetylation of NF-κB/p65. Cancer Lett. 2016;376:22–33.

    Article  CAS  Google Scholar 

  35. Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, et al. Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene. 2014;33:2395–404.

    Article  CAS  Google Scholar 

  36. Zhang T, Hu J, Wang X, Zhao X, Li Z, Niu J, et al. MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway. J Hepatol. 2019;70:87–96.

    Article  CAS  Google Scholar 

  37. Sociali G, Galeno L, Parenti MD, Grozio A, Bauer I, Passalacqua M, et al. Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics. Eur J Med Chem. 2015;102:530–9.

    Article  CAS  Google Scholar 

  38. Liu B, Xu L, Yu X, Li W, Sun X, Xiao S, et al. Protective effect of KLF15 on vascular endothelial dysfunction induced by TNF‑α. Mol Med Rep. 2018;18:1987–94.

    CAS  Google Scholar 

  39. Kobelt D, Zhang C, Clayton-Lucey IA, Glauben R, Voss C, Siegmund B, et al. Pro-inflammatory TNF-α and IFN-γ promote tumor growth and metastasis via induction of MACC1. Front Immunol. 2020;11:980.

    Article  CAS  Google Scholar 

  40. De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP, et al. Reversal of Warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR signaling pathways in non-small cell lung cancer. Clin Cancer Res. 2015;21:5110–20.

    Article  Google Scholar 

  41. Tian M, Chen XS, Li LY, Wu HZ, Zeng D, Wang XL, et al. Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis. Acta Pharm Sin. 2021;42:1180–9.

    Article  CAS  Google Scholar 

  42. Sizemore ST, Zhang M, Cho JH, Sizemore GM, Hurwitz B, Kaur B, et al. Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair. Cell Res. 2018;28:1090–102.

    Article  CAS  Google Scholar 

  43. Shanmugasundaram K, Nayak BK, Friedrichs WE, Kaushik D, Rodriguez R, Block K. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance. Nat Commun. 2017;8:997.

    Article  Google Scholar 

  44. Nie H, Ju H, Fan J, Shi X, Cheng Y, Cang X, et al. O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth. Nat Commun. 2020;11:36.

    Article  CAS  Google Scholar 

  45. Wang S, Jiang B, Zhang T, Liu L, Wang Y, Wang Y, et al. Insulin and mTOR pathway regulate HDAC3-mediated deacetylation and activation of PGK1. PLoS Biol. 2015;13:e1002243.

    Article  Google Scholar 

  46. Hu H, Zhu W, Qin J, Chen M, Gong L, Li L, et al. Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology. 2017;65:515–28.

    Article  CAS  Google Scholar 

  47. Zhang Y, Yu G, Chu H, Wang X, Xiong L, Cai G, et al. Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis. Mol Cell. 2018;71:201.e207.

    Article  CAS  Google Scholar 

  48. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018;37:1949–60.

    Article  CAS  Google Scholar 

  49. Miller JJ, Fink A, Banagis JA, Nagashima H, Subramanian M, Lee CK, et al. Sirtuin activation targets IDH-mutant tumors. Neuro Oncol. 2021;23:53–62.

    Article  CAS  Google Scholar 

  50. Biedermann J, Preussler M, Conde M, Peitzsch M, Richter S, Wiedemuth R, et al. Mutant IDH1 differently affects redox state and metabolism in glial cells of normal and tumor origin. Cancers (Basel). 2019;11:2028.

    Article  CAS  Google Scholar 

  51. Xu F, Hua Q, Zhang A, Di Z, Wang Y, Zhao L, et al. LncRNA AC020978 facilitates non-small cell lung cancer progression by interacting with malate dehydrogenase 2 and activating the AKT pathway. Cancer Sci. 2021;112:4501–14.

    Article  CAS  Google Scholar 

  52. Pramono AA, Rather GM, Herman H, Lestari K, Bertino JR. NAD- and NADPH-contributing enzymes as therapeutic targets in cancer: an overview. Biomolecules. 2020;10:358.

    Article  CAS  Google Scholar 

  53. Huang J, Tseng LH, Parini V, Lokhandwala PM, Pallavajjala A, Rodriguez E, et al. IDH1 and IDH2 mutations in colorectal cancers. Am J Clin Pathol. 2021;156:777–86.

    Article  CAS  Google Scholar 

  54. Yaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A, Sanchez-Vega F, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125.e123.

    Article  CAS  Google Scholar 

  55. Han CJ, Zheng JY, Sun L, Yang HC, Cao ZQ, Zhang XH, et al. The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway. Acta Pharm Sin. 2019;40:1292–302.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant No.81903065, 81830052, 82127807, 82003142), Construction project of Shanghai Key Laboratory of Molecular Imaging (18DZ2260400), “Chen Guang” project (No. 19CG75) supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation, the Natural Science Foundation of Shanghai (Grant No.21ZR1458900), and the Nurture projects for the Youth Medical Talents-Medical Imaging Practitioners Program (Grant No. SHWRS(2020)_087).

Author information

Authors and Affiliations

  1. Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China

    Hao Yang, Mingming Jin, Xiyu Liu, Xufeng Yao, Xinyi Mao, Nan Li, Beibei Liang, Wei Xie, Kunchi Zhang, Jian Zhao & Gang Huang

  2. Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Xiaoping Zhao, Jianjun Liu & Gang Huang

  3. Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201800, China

    Jun Yan

  4. Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Liu Liu

Authors
  1. Hao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoping Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianjun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingming Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xufeng Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xinyi Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Beibei Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kunchi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Liu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HY did experiments, data analysis and manuscript writing. XZ and JL did experiments and manuscript writing. MJ, XL, JY, ZZ, XM, NL and BL did experiments and data analysis. WX and KZ were responsible for clinical sample collection and statistics. JZ, LL and GH designed the experiments and revised the manuscript. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Jian Zhao, Liu Liu or Gang Huang.

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.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) 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

Yang, H., Zhao, X., Liu, J. et al. TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity. Oncogene 42, 35–48 (2023). https://doi.org/10.1038/s41388-022-02528-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02528-y

Search

Advanced search

Quick links