Yang Hao, Zhao Xiaoping, Liu Jianjun, Jin Mingming, Liu Xiyu, Yan Jun, Yao Xufeng, Mao Xinyi, Li Nan, Liang Beibei, Xie Wei, Zhang Kunchi, Zhao Jian, Liu Liu, Huang Gang
Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Oncogene. 2023 Jan;42(1):35-48. doi: 10.1038/s41388-022-02528-y. Epub 2022 Nov 10.
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.
结直肠癌（CRC）的异质性和耐药性常常导致治疗失败。异柠檬酸脱氢酶1（IDH1）作为三羧酸循环中的限速酶，可调节细胞内氧化还原环境，并介导肿瘤细胞对化疗药物的耐药性。本研究旨在阐明在肿瘤坏死因子α（TNFα）诱导下，IDH1乙酰化参与CRC耐药发生的潜在机制。我们发现TNFα破坏了沉默调节蛋白1（SIRT1）与IDH1之间的相互作用，并增加了IDH1第115位赖氨酸（K115）的乙酰化水平。K115的高乙酰化伴随着蛋白质泛素化，与IDH1 K115R相比，这增加了其被降解的易感性。TNFα介导的K115高乙酰化使CRC细胞对5-氟尿嘧啶（5FU）敏感，并使烟酰胺腺嘌呤二核苷酸磷酸（NADPH）/烟酰胺腺嘌呤二核苷酸磷酸（NADP）比值降至细胞内活性氧（ROS）的水平。此外，TNFα和5FU在体内抑制CRC肿瘤生长，而表达K115R的肿瘤组织则产生了5FU耐药性。在人类CRC组织中，K115乙酰化与TNFα浸润呈正相关，与化疗诱导的去乙酰化相比，K115高乙酰化与良好的预后相关。因此，TNFα诱导的IDH1第115位点高乙酰化促进了CRC细胞中的抗肿瘤氧化还原稳态，并可作为预测CRC患者化疗反应的标志物。
