DBC1调节SIRT1功能的机制研究及其在肝癌发生的作用

SIRT1是一种NAD+依赖型去乙酰化酶。 SIRT1通过去乙酰化不同的底物，参与调控多种生物学过程。DBC1作为SIRT1的负调节因子通过结合SIRT1催化区域抑制SIRT1活性，本项目拟通过串联亲和纯化，免疫共沉淀，细胞凋亡检测等分子生物学手段研究DNA损伤刺激能否诱导DBC1磷酸化，并通过磷酸化DBC1增强DBC1-SIRT1结合从而进一步抑制SIRT1活性及其抗凋亡功能。SIRT1的抗凋亡功能与肿瘤发生密切相关，申请人前期工作发现在细胞水平及动物模型水平SIRT1能加快肝癌细胞的增殖，进一步拟在细胞水平及动物模型水平上研究DBC1是否通过SIRT1调控肝癌发生，并以DBC1-SIRT1互作区域为靶点设计模拟多肽获得SIRT1的小分子抑制剂，研究其单独或联合肝癌药物对肿瘤的杀伤效果，为肝癌的治疗提供新的理论依据，为转化医学的研究提供新思路。

SIRT1 is a NAD+ dependent deacetylase. SIRT1 regulates multiply cellular processes through deacetylating different factors. DBC1, function as SIRT1 negative regulator, inhibits SIRT1 activity through binding to SIRT1's enzyme domain. Our project will study if cellular stress can induce phosphorlation of DBC1, which in turn increases DBC1-SIRT1 binding and further inhibits SIRT1 dependent anti-apoptosis function. Previous study suggested SIRT1's anti-apoptosis function is related to tumorigenesis. Our cell proliferation assay data and nude mice xenograft model data both showed SIRT1 increased liver cancer cell growth. We will further study the role of DBC1 in SIRT1-induced hepatocarcinogenesis. Furthermore, we will design mimic peptide according to the DBC1-SIRT1 interaction domain and discover the SIRT1 small molecular inhibitor. Next, we will test the chemotherapy efficiency by using the mimic peptide singly or together with other chemotherapy drugs. Take together, this study will bring new clue on liver cancer chemotherapy.