TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity.
Hao YangXiaoping ZhaoJianjun LiuMingming JinXiyu LiuJun YanXufeng YaoXinyi MaoNan LiBeibei LiangWei XieKunchi ZhangJian ZhaoLiu LiuGang HuangPublished in: Oncogene (2022)
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.
Keyphrases
- rheumatoid arthritis
- low grade
- wild type
- induced apoptosis
- reactive oxygen species
- end stage renal disease
- gene expression
- chemotherapy induced
- single cell
- chronic kidney disease
- cell cycle arrest
- diabetic rats
- high glucose
- squamous cell carcinoma
- dna damage
- newly diagnosed
- radiation therapy
- drug induced
- peritoneal dialysis
- prognostic factors
- mesenchymal stem cells
- endoplasmic reticulum stress
- amino acid
- patient reported outcomes
- pluripotent stem cells