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

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.

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。

CDK抑制剂p21与细胞增殖、衰老及肿瘤发生等多种生物学过程密切相关，但其作用机制尚需进一步探讨。本项目证实转录因子HBP1可激活p21活性，参与了细胞衰老和肿瘤发生过程。HBP1一方面可抑制MDM2对p53蛋白的泛素化，提高p53对p21的转录激活作用；另一方面，HBP1通过Wnt/β-catenin信号通路，抑制EZH2基因表达，抑制p21 promoter区组蛋白甲基化，促进p21基因表达。总之，HBP1通过调节MDM2/p53和Wnt/β-catenin/EZH2信号通路，上调p21基因表达，促进细胞衰老，抑制肿瘤发生。本研究证实转录因子HBP1通过调节蛋白质泛素化和组蛋白甲基化修饰，在细胞衰老和肿瘤发生过程中起着重要的作用。