表观遗传因子SIRT7介导的肝癌药物抗性的分子机制及靶向性研究

药物抗性是制约肝癌治疗效果的关键节点，阐明其分子机制并开发分子靶向药物因此显得尤为重要。前提研究提示SIRT7在肝癌中高表达并与化疗药物抗性正相关，敲低SIRT7显著抑制肿瘤生长并提高化疗敏感性。机制层面，SIRT7诱导p53去乙酰化而调节p53介导的NOXA表达，抑制化疗药物诱导的肝癌细胞凋亡。我们推断SIRT7是调控肝癌生长及化疗药物抗性的关键因子，抑制SIRT7活性能抑制肿瘤生长并提高肝癌化疗敏感性。本课题拟首先阐明SIRT7调节p53活性的分子机制并明确p53去乙酰化位点，明确NOXA在SIRT7介导的药物抗性中的作用，并用临床样本确认；进一步探究SIRT7在HCC中的作用，明确其在肝癌中调控的重要通路及关键靶基因；研发SIRT7小分子抑制剂并验证其在抗肿瘤以及与化疗药物联用的增效作用。本课题将进一步阐明肝癌发展跟药物抗性的分子机制，并为以SIRT7为靶点的肝癌治疗提供实验依据。

Optimal therapeutic strategies for hepatocellular carcinoma (HCC) patients are still challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Growing evidence shows that genetic and epigenetic alterations are involved in HCC progression and resistance to therapy, however，the molecular mechanisms underlying resistance to therapy have not been fully understood. Our preliminary data indicated that SIRT7 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with TACE-resistance and poor survival (p<0.008.) Depletion of SIRT7 from multiple liver cancer cell lines significantly decreased cell proliferation and increased doxorubicin toxicity. At the molecular level, we observed that SIRT7 interacts with and induces deacetylation of p53. Deacetylated p53 showed significantly less affinity for the NOXA promoter and its transcription. SIRT7 suppression increased doxorubicin induced p53 activation, inhibited tumor growth and induced apoptosis. We thus hypothesis that SIRT7 plays critical role in regulating liver cancer chemosensitivity, targeting and represents a novel potential therapeutic target for HCC treatment. In this proposal, we will first investigate mechanism of SIRT7 regulates p53 activity and identify SIRT7 mediated deacetylation site of p53. Investigate the role of NOXA in SIRT7 mediated chemosensitivity. We will confirm our finding in clinical human specimens. In addition, we will further investigate the role of SIRT7 in HCC and identify novel SIRT7 targeting signaling pathway and target genes by using mRNA sequencing and bioinformatics tools. Finally, we will develop SIRT7 specific small molecular compound and evaluate its effects on liver cancer growth and chemosensitivity both in vitro and in mouse model. Successfully finish this project will not only provide insightful mechanisms that underlying liver cancer pathogenesis and chemosensitivity but also will generate experimental data for developing novel therapeutic strategies for HCC.