PDF(Pubmed)
Abstract：
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly tumors; however, its pathogenic mechanism remains largely elusive. In-depth researches are needed to reveal the expression regulatory mechanisms and functions of the RNA-binding protein RALY in HCC. Here, we identify RALY as a highly expressed oncogenic factor that affects HCC cells proliferation both in vitro and in vivo. O-GlcNAcylation of RALY at Ser176 enhances its stability by protecting RALY from TRIM27-mediated ubiquitination, thus maintaining hyper-expression of the RALY protein. Mechanistically, RALY interacts with USP22 messenger RNA, as revealed by RNA immunoprecipitation, to increase their cytoplasmic localization and protein expression, thereby promoting the proliferation of HCC cells. Furthermore, we develop a novel RALY protein degrader based on peptide proteolysis-targeting chimeras, named RALY-PROTAC, which we chemically synthesize by linking a RALY-targeting peptide with the E3 ubiquitin ligase recruitment ligand pomalidomide. In conclusion, our findings demonstrate a novel mechanism by which O-GlcNAcylation/RALY/USP22 mRNA axis aggravates HCC cells proliferation. RALY-PROTACs as degraders of the RALY protein exhibit potential as therapeutic drugs for RALY-overexpressing HCC.
摘要：
肝细胞癌(HCC)是最常见和最致命的肿瘤之一;然而,其致病机制在很大程度上仍然难以捉摸。需要深入研究RNA结合蛋白RALY在肝癌中的表达调控机制和功能。这里,我们确定RALY是一种高表达的致癌因子，在体外和体内都会影响HCC细胞的增殖。RALY在Ser176的O-GlcNAcylation通过保护RALY免受TRIM27介导的泛素化作用来增强其稳定性，从而维持RALY蛋白的高表达。机械上,RALY与USP22信使RNA相互作用，正如RNA免疫沉淀所揭示的，增加它们的细胞质定位和蛋白质表达，从而促进HCC细胞的增殖。此外，我们开发了一种基于肽蛋白水解靶向嵌合体的新型RALY蛋白降解剂，名为RALY-PROTAC,我们通过将RALY靶向肽与E3泛素连接酶募集配体泊马度胺连接来化学合成。总之,我们的发现证明了O-GlcNAcylation/RALY/USP22mRNA轴加重HCC细胞增殖的新机制。RALY-PROTACs作为RALY蛋白的降解剂显示出作为RALY过表达HCC的治疗药物的潜力。
