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

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

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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.

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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.

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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).

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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

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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.

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Correspondence to Jian Zhao, Liu Liu or Gang Huang.

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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

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