RNA结合蛋白RBM8A在肝癌发展中的作用及机制研究

肝癌是我国死亡率最高的消化道恶性肿瘤，发展迅速是导致其预后差的重要因素。RBM8A是一种RNA结合蛋白，可结合RNA发挥转录后调控作用。申请人报道了其高表达促进肝癌发展，但目前其中的具体机制尚不清楚。生物信息学分析提示组蛋白去乙酰化酶9(HDAC9)是RBM8A下游关键调节因子，将其敲低后逆转了RBM8A介导的肝癌恶性表型。预实验发现RBM8A与HDAC9的mRNA结合，在转录后水平调控其表达。进而挖掘生信数据显示p16是RBM8A/HDAC9轴潜在调控的下游抑癌基因。深入研究发现RBM8A通过HDAC9介导p16启动子的组蛋白去乙酰化。据此提出假说“RBM8A通过转录后调控HDAC9介导组蛋白去乙酰化，抑制p16转录进而促进肝癌发展”。本项目拟通过体外细胞实验、体内动物模型和肝癌临床样本，多层次地深入研究其具体机制，旨在阐明RBM8A与肝癌发展的潜在关系，有望为肝癌治疗提供新的分子靶点。

Hepatocellular carcinoma (HCC) has the highest mortality rate with poor prognosis amongst gastrointestinal malignancies in Chinese population, particularly due to its aggressive progression. RBM8A, a member of the RNA binding proteins family (RBPs) plays a fundamental role in the post-transcriptional control of gene expression and regulatory functions in many physiological and pathological processes. Our previous study reported that high expression of RBM8A correlated with poor HCC prognosis. However, its underlying molecular mechanism remains elusive and to be further investigated. Bioinformatics analysis revealed that HDAC9 was an important regulator of multiple RBM8A downstream genes and signal pathways. Our preliminary experiments suggested that knocking down of HDAC9 rescued the malignant phenotype of HCC mediated by RBM8A. Meanwhile, we found that RBM8A directly bound to HDAC9 mRNA and increased its protein level post-transcriptionally. Intriguingly, further bioinformatics analysis revealed that p16 was the downstream tumor suppressor gene of RBM8A/HDAC9 axis. Furthermore, we found that RBM8A could induced histone deacetylation of p16 promoter through HDAC9. Taken together, our study suggested that RBM8A mediated histone deacetylation through post-transcriptionally modulating HDAC9, then inhibited p16 transcription and contributed to HCC progression. This study sheds lights on the functions and potential molecular mechanisms of RBM8A in HCC progression through in vitro and in vivo studies as well as human HCC sample. Molecules implicated in this pathway might serve as novel therapeutic targets for HCC treatment.