转录因子HBP1对组蛋白甲基转移酶EZH2的调控及其生物学意义

项目名称： 转录因子HBP1对组蛋白甲基转移酶EZH2的调控及其生物学意义

项目编号： No.31471292

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 张晓伟

作者单位： 北京大学

项目金额： 90万元

中文摘要： 在早期癌症转化过程中，诱导细胞早老是抑制肿瘤发生的重要机制之一。转录因子HBP1是在细胞衰老和肿瘤发生过程中均发挥作用的双重活性的调控因子，但其作用机制不清。我们的研究初步证实HBP1通过抑制Wnt信号通路来抑制组蛋白甲基转移酶EZH2基因的表达。EZH2可以使组蛋白H3K27三甲基化，调节染色质DNA致密性，从而抑制许多基因的转录，在细胞增殖过程中起着重要的作用。我们初步证实HBP1对EZH2的抑制作用可以使Wnt通路抑制因子SFRP1表达上调，从而进一步增强对Wnt通路的抑制，形成正反馈信号通路，并且这条信号通路可能参与了HBP1诱导的细胞衰老过程。本研究将深入探讨HBP1对EZH2的调控机制，以及由此而形成的正反馈信号通路的作用机制、这条信号通路在细胞衰老和转化中的作用。此研究将为探索衰老及肿瘤转化的本质提供理论与实验依据。

中文关键词： 转录因子；组蛋白甲基化；细胞衰老；细胞转化；信号转导

英文摘要： Premature senescence is a potential tumor-suppressive mechanism in early cancer transitions. Transcription factor HBP1 is a dual factor in senescence and tumorigenesis, but the mechanism of its regulation is not clear. Our data tentatively demonstrated that HBP1 inhibits the expression of histone methyltransferase EZH2 through repressing Wnt signaling pathway. EZH2 trimethylates histone H3K27, as a catalytic subunit of PRC2 (one complex of PcG protein), resulting in condensation of chromatin DNA and transcription inhibition of many genes. EZH2 plays an important role in cellular proliferation.We tentatively indicated that the inhibition of EZH2 by HBP1 up-regulates expression of SFRP1 which is an inhibitor factor for Wnt signaling pathway, resulting in enhancing the inhibition of Wnt signaling, forming a positive axis in signal transduction. Furthermore, it was demonstrated that the positive axis might particate in HBP1-induced premature senescence. In this study, we will explore thoroughly the regulation mechanisms of EZH2 by HBP1 and the positive axis of HBP1-Wnt signaling-EZH2-SFRP1-Wnt signaling,as well as its roles in cell senescence and transformation. The investigation will provide theorial and experimental basis for exploring the characteristic essence of senescence and tumor transformation.

英文关键词： transcription factor;histone methylation;cell senescence;cell transformation;signal transduction