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Abstract：
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 UBC9. 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.
摘要：
化疗耐药是化疗失败和肿瘤复发的主要原因。整体蛋白SUMO化对大肠癌（CRC）化疗耐药的影响仍有待研究。在这里，我们提出，升高的SUMO2/3修饰的蛋白质赋予CRC中的5-氟尿嘧啶（5-FU）化学耐药性获得。与正常结肠细胞系NCM460相比，CRC细胞系中整体蛋白的SUMO化水平升高。5-FU处理明显降低5-FU敏感性CRC细胞(包括HT29、HCT116和HCT-8)中整体蛋白的SUMO化。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暴露下以浓度依赖性方式增加。5-FU处理结合SUMO化抑制剂ML-792显著增加了5-FU抗性细胞对5-FU的敏感性并减少了HCT-8/5-FU细胞中的集落形成数。UBC9介导的SUMO化升高有助于HCT116细胞的5-FU抗性。此外，我们还通过与UBC9的启动子直接结合,将RREB1鉴定为全局细胞蛋白SUMO化分析的调节因子.RREB1过表达促进CRC的5-FU抗性,通过抑制剂ML-792的治疗部分废除。总之,RREB1增强的蛋白质SUMO化有助于在CRC中获得5-FU抗性。
