PSMD14介导PRMT4去泛素化调控肝癌发生发展的机制研究

Deubiquitinase-mediated protein posttranslational modification is closely associated with cancer progression. However, the functions, interacting proteins and the regulatory mechanism of target genes of PSMD14 in hepatocellular carcinoma (HCC) remain poorly understood. Our present study showed that PSMD14 expression was significantly increased in HCC samples, and promoted HCC growth and metastasis. Our preliminary results showed that PSMD14 interacted with histone arginine methyltransferase 4 (PRMT4), and promoted its stability. We also found that PSMD14 increased WDR76, RAB23 and WIPF1 transcription through modulating the H3R17me2 and H3R26me2 level across their promoter regions. Thus, in this study, we will reveal the molecular mechanism by which PSMD14 regulates PRMT4 deubiquitination, and determine the PSMD14-PRMT4-induced biological behavior and downstream target genes, and explore the epigenetic mechanism by which PSMD14 regulates target genes expression, and reveal the clinical significance of PSMD14-PRMT4 axis, and determine the possible clinical therapeutic effect of HCC targeting PSMD14-PRMT4 axis. In the study, we will reveal the molecular network mediated by PSMD14 in HCC occurence and development, which is important for the potential treatment of HCC.

去泛素化酶介导的蛋白翻译后修饰与肿瘤密切相关，然而去泛素化酶PSMD14在肝癌中的功能、相互作用的蛋白及调控下游基因表达的分子机制尚未完全阐明。我们前期发现：PSMD14在肝癌中高表达，并促进肝癌生长和转移；PSMD14能去泛素化组蛋白精氨酸甲基转移酶PRMT4，促进其蛋白稳定性；PSMD14影响WDR76、RAB23和WIPF1等下游基因的转录及启动子H3R17me2和H3R26me2表达水平。本研究将进一步明确PSMD14调控PRMT4去泛素化的机制；明确PSMD14-PRMT4介导的生物学行为及调控的下游基因；明确PSMD14通过PRMT4调控下游基因转录的表观遗传学机制；明确PSMD14-PRMT4轴的临床病理意义；初步探讨以PSMD14-PRMT4轴作为肝癌治疗靶点的效果。阐明PSMD14所调控的关键分子网络在肝癌发生发展中的作用，为肝癌的治疗提供理论依据。

原发性肝癌是全球最常见的恶性肿瘤之一，是世界第二高致死率的癌症。近年来研究发现，异常的蛋白质泛素化修饰和组蛋白精氨酸甲基化均在癌症的发生和发展中起重要作用。在本研究中，我们发现PSMD14可与组蛋白精氨酸甲基转移酶CARM1（PRMT4）结合，促进CARM1发生去泛素化，从而抑制CARM1的降解，上调CARM1表达水平。同时，我们新发现FERMT1为CARM1的下游基因，参与调控肝癌EMT过程。最后，我们发现靶向CARM1的小分子抑制剂SGC2085能显著抑制肝癌细胞的增殖和转移能力。综上，我们揭示了PSMD14-CARM1-FERMT1轴的促癌作用和机制，为以PSMD14、CARM1作为治疗肝癌的有效靶点提供了理论证据。