去乙酰化酶SirT7在应激反应及肿瘤细胞死亡中的作用及调控研究

The Sirtuins (SirT1 to SirT7) are a family of protein deacetylase that closely linked to aging, tumor and metabolism disorder diseases. We have previously reported a role for SirT1 in cancer drug resistance, and revealed signaling pathways regulating SirT1 phosphorylation and degradation and their roles in mediating autophagy and autophagy-dependent lipid degradation in liver. SirT7, the only deacetylase found to be localized in the nucleous, is less studied. In recent years SirT7 is found closely related to cancer and lipid metabolism disorders. Howerver SirT7 downstream targets remain largely unknown, and how SirT7 activity and degradation are regulated need to be elucidated. Our primary studies identified that SirT7 can be modified by phosphorylation and its subcellular localization changed markedly under various stress conditions, phosphorylation may regulate SirT7 subcellular distribution and degradation, REGγ proteasome promotes SirT7 degradation, and REGγ deficicency may promote an engery-dependent tumor cell death under starvation, SirT7 may also interact with some new important DNA damage and cell death regulating proteins. In this proposal we plan to study the role of REGγ-SirT7 interaction in regulationg cellular homeostasis and tumor cell death, understanding the regulatory mechanisms and functions of SirT7 phosphorylation and degradation, revealing the functional interplay between SirT7 and its new interacting proteins in regulating cell stress response , with aims to provide clues to new ways to cancer therapy.

Sirtuins（SirT1至SirT7）是一类与衰老、癌症和代谢紊乱疾病相关的去乙酰化酶。申请人前期报道SirT1参与肿瘤耐药，发现SirT1的修饰和降解机制及其如何调控自噬及自噬依赖的肝脏脂肪代谢。与其它Sirtuin不同，SirT7主要在核仁分布。近期发现SirT7与肿瘤和脂代谢紊乱相关。但SirT7底物蛋白发现非常有限、其酶活性调控及降解研究几乎为空白。申请人发现：多种外界压力可诱发SirT7磷酸化和细胞亚定位变化；SirT7磷酸化可调控其定位和降解，SirT7的rDNA转录活性和降解受REGγ蛋白酶体调控，REGγ缺失可诱发能量依赖的肿瘤饿死现象；SirT7可与一些DNA损伤和死亡调控蛋白结合。本课题拟研究SirT7磷酸化和降解机制，阐释REGγ-SirT7相互作用如何调控细胞能量稳态和肿瘤饿死，并探讨SirT7如何与新结合蛋白作用并调控细胞应激，为肿瘤治疗提供新理论和新思路。

Sirtuins（从SirT1至SirT7）家族蛋白通过靶蛋白去乙酰化修饰，广泛参与了能量代谢、细胞应激、衰老及癌症调控。申请人前期报道了SirT1参与肿瘤耐药（NCB 2016），SirT1磷酸化修饰及降解如何调控自噬及脂肪肝 (Cell Metabolism 2013)。本课题的主要任务是研究Sirtuins及其相关因子在肿瘤细胞能量代谢、发生发展及耐药复发中的作用。围绕上述内容，课题主持人作为通讯作者，在Current Biology（2017）和Nature Communications (2016, 2021) 发表了代谢紊乱及肿瘤耐药复发相关的研究论文，并提交了1项SIRTUIN研究相关的国家发明专利（注册号：202011278356.3），其中通讯作者论文简述如下：.(1) 报道SIRT7磷酸化修饰调控参与能量限制情况下的肿瘤细胞生死命运决定(Nature Communications. 2016; 7:12497)。该论文内容符合本课题核心研究计划。.(2) 报道SIRT1磷酸化修饰通过去乙酰化修饰poly(A)-mRNA结合蛋白PABP1，参与能量限制情况下的细胞能量稳态调控（Current Biology. 2017; 27(15):2271-2284）。该论文被Nature Reviews Molecular Cell Biology杂志发表论文专评 (Stress responses: SIRT1 puts an embargo on mRNA export , Nature Reviews Molecular Cell Biology , 2017 , DOI: 10.1038/nrm.2017.82) , 点评我们发现的SIRT1对poly(A)-mRNA转移调控作用为能量代谢紊乱相关疾病药物研发提供了新途径。该论文内容符合本课题的能量限制应激研究计划。.(3)报道DNA损伤化疗药物如何激活中心体凝聚，诱发基因组不稳定，进而产生肿瘤耐药和复发（Nature Communications. 2021 Jan, 10.1038/s41467-020-20208-x）。该论文内容符合本课题的肿瘤药物应激研究内容。