HDAC3在IFN-γ诱导胃癌B7-H1表达中的调控机制研究

It is widely recognized that gastric cancer cells often overexpress B7-H1 to evade immunological cleansing. B7-H1 is a co-inhibitory ligand that can bind PD-1 on T cells to suppress T cell effector functions. However, the mechanism underlying B7-H1 expression remains poorly defined. Preliminary studies suggested that IFN-γ is the predominant inducing factor of B7-H1 expression. Histone acetylation is an important epigenetic process that regulates gene transcription and several studies showed that histone de-acetylases (HDACs) play a role in the IFN-γ induced inflammatory gene expression program. Our group found that, inhibition or knock-down of HDAC3 attenuates IFN-γ induced B7-H1 expression, which is contrary to the current notion that HDAC3 functions to suppress transcription. Based on obtained results, we propose two possible mechanisms: 1) HDAC3 suppresses a miRNA expression that targets JAK2, a key component of IFN-γ signaling pathway, to maintain the robust signal transduction； 2) HDAC3 binds to the promoter region of B7-H1 gene to balance the process of histone acetylation and de-acetylation to form a perfect condition for the transcription. Clarification of HDAC’s regulation of B7-H1 expression is the key to understanding B7-H1 specific transcription machine, and has important implications for clinical application because of the existence of well–defined HDAC inhibitors.

胃癌细胞高表达B7-H1，通过与T细胞上的PD-1结合，向T细胞传递抑制性信号以实现免疫逃逸。B7-H1在胃癌细胞中的表达调控是亟待阐明然而目前研究较少的领域。初步研究显示IFN-γ是肿瘤微环境中诱导B7-H1表达的主要因子，而组蛋白去乙酰化酶（HDAC）参与多种IFN-γ相关炎性基因表达的调控。我们课题组发现HDAC3在IFN-γ诱导B7-H1表达的过程中发挥重要的促进作用。在预实验基础上，我们提出HDAC3的作用机制假设：1.间接作用：HDAC3抑制靶向JAK2的miRNA表达，从而维持IFN-γ通路的正常传导；2.直接作用：HDAC3参与调节B7-H1启动子区域的组蛋白乙酰化稳态，防止过度乙酰化，促进转录进行。对HDAC3调控B7-H1表达机制的阐明，有助于为B7-H1抑制提供新的可行的靶点，为进一步的临床应用提供方向。

胃癌细胞高表达B7-H1，通过与T细胞上的PD-1结合，向T细胞传递抑制性信号以实现免疫逃逸。B7-H1在胃癌细胞中的表达调控是亟待阐明然而目前研究较少的领域。初步研究显示IFN -γ是肿瘤微环境中诱导B7-H1表达的主要因子，而组蛋白去乙酰化酶（HDAC）参与多种IFN-γ 相关炎性基因表达的调控。我们主要从3个方面做了相关工作：1、通过meta分析，证实了胃癌中B7-H1表达与预后不良相关；2.Chip-qPCR和co-IP显示IFN-γ 刺激引起HDAC3募集到B7-H1基因启动子区域，参与组蛋白乙酰化调控；3.定量乙酰化修饰蛋白质组学显示胃癌和癌旁组织具有大量差异表达水平蛋白，为进一步筛选参与胃癌发展过程的非组蛋白乙酰化提供了基础。