Deng Ya-Nan, Chen Ying, Gao Shan, Zhang Nan, Luo Yinheng, Luo Shu, Li Qiu, Fu Xianghui, Liang Shufang
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Department of Medical Oncology, Suining First People's Hospital, Suining, Sichuan, China.
Front Pharmacol. 2024 Jul 23;15:1381860. doi: 10.3389/fphar.2024.1381860. eCollection 2024.
Chemoresistance is a main cause of chemotherapy failure and tumor recurrence. The effects of global protein SUMOylation on chemoresistance in colorectal cancer (CRC) remains to be investigated. Herein, we have proposed that the elevated SUMO2/3-modified proteins confer 5-fluorouracil (5-FU) chemoresistance acquisition in CRC. The SUMOylation levels of global proteins in CRC cell lines were elevated compared with normal colon cell line NCM460. 5-FU treatment obviously reduced SUMOylation of global proteins in 5-FU-sensitive CRC cells including HT29, HCT116 and HCT-8. However, in 5-FU-resistant HCT-8/5-FU cells, the expression level of SUMO2/3-modified proteins was increased under 5-FU exposure in a concentration-dependent manner. 5-FU treatment combined with SUMOylation inhibitor ML-792 significantly increased the sensitivity of 5-FU-resistant cells to 5-FU and reduced colony formation numbers in HCT-8/5-FU cells. And UBC9-mediated SUMOylation elevation contributes to 5-FU resistance in HCT116 cells. Moreover, we also identified RREB1 as a regulator of SUMOylation profiling of global cellular proteins via directly binding to the promoter of . Overexpression of RREB1 promoted 5-FU resistance in CRC, which was partially abolished by treatment of inhibitor ML-792. In conclusion, RREB1-enhanced protein SUMOylation contributes to 5-FU resistance acquisition in CRC.
化疗耐药是化疗失败和肿瘤复发的主要原因。整体蛋白质SUMO化修饰对结直肠癌（CRC）化疗耐药的影响仍有待研究。在此，我们提出SUMO2/3修饰蛋白水平升高赋予CRC细胞对5-氟尿嘧啶（5-FU）的化疗耐药性。与正常结肠细胞系NCM460相比，CRC细胞系中整体蛋白质的SUMO化水平升高。5-FU处理明显降低了包括HT29、HCT116和HCT-8在内的5-FU敏感CRC细胞中整体蛋白质的SUMO化修饰。然而，在5-FU耐药的HCT-8/5-FU细胞中，SUMO2/3修饰蛋白的表达水平在5-FU暴露下呈浓度依赖性增加。5-FU处理联合SUMO化抑制剂ML-792显著增加了5-FU耐药细胞对5-FU的敏感性，并减少了HCT-8/5-FU细胞中的集落形成数量。并且UBC9介导的SUMO化水平升高促成了HCT116细胞对5-FU的耐药性。此外，我们还通过直接结合 的启动子鉴定出RREB1是整体细胞蛋白质SUMO化修饰谱的调节因子。RREB1的过表达促进了CRC对5-FU的耐药性，而抑制剂ML-792处理可部分消除这种耐药性。总之，RREB1增强的蛋白质SUMO化修饰促成了CRC对5-FU的耐药性获得。
