分子伴侣HSP90与辅因子CHIP共调节METTL3泛素化和RNA m6A修饰的机制与功能

METTL3是负责RNA m6A修饰的甲基转移酶。METTL3与METTL14装配形成功能性复合体，并调节RNA剪接、翻译和代谢；以及性别决定、胚胎发育和肿瘤发生等过程。我们发现METTL3是分子伴侣HSP90的底物蛋白；HSP90辅因子CHIP调节METTL3泛素化和降解；METTL14抑制CHIP对METTL3的负调控；用小分子化合物抑制HSP90，可诱导METTL3降解并抑制METTL3-METTL14复合体的装配。HSP90在很多癌细胞中高表达并促进肿瘤发生。本项目以结直肠癌肿瘤发生为研究模型，综合运用生化分子和细胞生物学方法并结合组学研究，深入阐明HSP90抑制剂调节METTL3-METTL14复合体折叠、装配、活性和降解等过程的分子机制，及其对复合体下游分子网络和癌生物学特征的影响，为HSP90抑制剂的抗癌研究和药效评价等提供更全面的理论依据，促进精准医学和个体化治疗的进展。

METTL3 is the major methyltransferase of RNA m6A methylation. METTL3 interacts with METTL14 to form a functional RNA methyltransferase protein complex. METTL3/METTL14 complex regulates RNA splicing、protein translation and RNA turnover, it also involved in many biological process, such as sex determination, embryonic development and tumorigenesis. In our group, we already proved that METTL3 is a client protein of molecular chaperone HSP90; the HSP90 co-chaperone CHIP mediates METTL3 ubiquitination and degradation through proteasome pathway; and the downregulation of METTL3 by CHIP can be inhibited by METTL14. Furthermore, we found that the small molecule compound inhibitors of HSP90, such as 17-AAG and PU-H71, can efficiently induce METTL3 ubiquitination and degradation, thus decrease METTL3-METTL14 complex formation. HSP90 usually has highly expression in cancer cells to maintain onco-protein 3-D structure and stability. HSP90 inhibitors are potential anti-cancer drug. We hope that with the support of this project, we can figure out the molecular details of how HSP90 inhibitors regulate METTL3 folding、ubiquitination、degradation and METTL3-METTL14 complex assembly in colorectal cancer cells. Definitely works like that will greatly improve the way we treat cancer.