抑癌基因PTEN在组蛋白脱乙酰酶抑制剂抗肿瘤作用中的作用

项目名称： 抑癌基因PTEN在组蛋白脱乙酰酶抑制剂抗肿瘤作用中的作用

项目编号： No.81472764

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 甘业华

作者单位： 北京大学

项目金额： 75万元

中文摘要： PTEN是重要的抑癌基因，通过负调控PI3K/AKT通路，抑制细胞增殖，促进细胞凋亡。PTEN在多种肿瘤中有突变、缺失或表达下调。PTEN的激活机制尚未完全明了。蛋白乙酰化是蛋白翻译后重要的修饰，可影响蛋白功能。组蛋白脱乙酰酶抑制剂（HDACi）除可上调组蛋白乙酰化外，还可上调其他蛋白乙酰化，是潜在的抗肿瘤药物，已被应用于治疗皮肤T细胞淋巴瘤。本课题组曾报道HDACi可通过促进PTEN膜转位，即激活PTEN，诱导肿瘤细胞凋亡。但HDACi激活PTEN以及PTEN在HDACi抗肿瘤作用中的作用尚未阐明。本研究拟主要探讨HDACi促进PTEN膜转位是否依赖PTEN乙酰化，将明确其乙酰化位点及特定的组蛋白脱乙酰酶，并功能性评估PTEN乙酰化在HDACi抗肿瘤中的作用。本研究将有助于进一步了解PTEN的调控及HDACi抗肿瘤机制；为HDACi临床应用或开发新的HDACi抗肿瘤药，提供实验依据。

中文关键词： C01_口腔肿瘤；PTEN；组蛋白脱乙酰酶抑制剂；乙酰化；抑癌基因

英文摘要： PTEN is an important tumor suppressor and involves in cell cycle arrest and apoptosis through negative regulation of PI3K/AKT signal pathway. PTEN was found mutated, deleted or downregulated in many tumors. The activation of PTEN remains to be fully understood. Acetylation is an important post-translational modification and influences the functions of proteins. Histone deacetylase inhibitors (HDACi) not only upregulate acetylation of histone, but also upregulate acetylation of non-histone proteins. HDACi are potential antitumor drugs and one of HDACi, SAHA, has been approved by U.S. Food and Drug Administration for treatment of cutaneous T-cell lymphoma. It is reported by our group that HDACi can not upregulate expression of PTEN, and but also upregulate membrane translocation of PTEN, i.e., activation of PTEN. However, the mechanism underlying the activation of PTEN by HDACi and the role of PTEN in antitumor effects of HDACi remain to be explored. The purposes of this project are mainly to explore whether HDACi-induced membrane translocation of PTEN is dependent on acetylation of PTEN, if it is, which lysine in PTEN and which histone deacetylase are responsible for HDACi-induced acetylation of PTEN. The role of PTEN acetylation in the antitumor effects of HDACi is also to be functionally evaluated. The results of this project will help further understanding the regulation of PTEN and the mechanisms underlying the antitumor effects of HDACi, and will provide data for clinical selection of tumors without deletion or mutation of PTEN for HDACi treatment, and even for the development of new HDACi for cancer therapy.

英文关键词： PTEN;histone deacetylase inhibitor;acetylation;tumor suppressor;membrane translocation