C21orf58通过CyclinD1调控肝癌发生发展的机制研究

肝癌恶性高预后差，但其致恶和药物抵抗的确切机制尚不明确。研究报道细胞周期异常可介导一线药物索拉非尼抵抗，而细胞周期蛋白CyclinD1通过调控细胞周期促进肿瘤恶性生长，是治疗肝癌的潜在靶点。我们前期结果发现，C21orf58是CyclinD1上游的关键调控因子，在肝癌和索拉非尼耐药细胞中高表达，与不良预后相关；能结合并激活CyclinD1启动子，与HDAC1作用，提升启动子H3K27ac水平，促进肝癌细胞生长和增强索拉非尼抵抗。项目拟在已有基础上，从临床组织、细胞和动物层面明确C21orf58的功能，从调节H3K27ac的角度揭示其调控CyclinD1转录的机制，以C21orf58/CyclinD1信号为切入点阐明索拉非尼耐药原因，从细胞和动物水平明确C21orf58是治疗索拉非尼耐药肝癌的潜在靶点。本项目首次深入探索C21orf58的生物功能和机制，为临床有针对性的治疗肝癌提供新思路。

Hepatocellular carcinoma (HCC) has a high degree of malignancy and poor prognosis, but the exact mechanisms of its malignancy and drug resistance remain unclear. It is reported that abnormal cell cycle leads to the resistance of sorafenib in HCC, while cyclinD1 promotes the cell cycle and accelerates the malignant growth of cancers, suggesting that cyclinD1 is a potential target for HCC treatment. In this study, we found that C21orf58 was an important regulatory factor upstream of CyclinD1, highly expressed in clinical HCC tissues and sorafenib-resistant HCC cells, and associated with poor prognosis. C21orf58 could bind to and activate the CyclinD1 promoter, interact with HDAC1, increase the level of H3K27ac in promoter, promote the cell growth and enhance sorafenib resistance of HCC cells. Based on these data, we plan to further investigate the malignant function of C21orf58 by using clinical tissues, cell and mouse models, reveal the molecular mechanism of CyclinD1 transcriptional activation regulated by modulating the level of H3K27ac on CyclinD1 promoter, clarify that activation of C21orf58/CyclinD1 signaling is the cause of enhancing sorafenib resistance and C21orf58 is a potential target for the treatment of sorafenib-resistant HCC. This study first explores the biological function and mechanism of C21orf58, and provides a new idea for clinical targeted therapy of HCC.