靶向EZH2诱发骨髓瘤细胞自噬过程中H3K27me3与hMOF/H4K16ac交互调控机制研究

组蛋白修饰异常及自噬调控紊乱可诱发肿瘤。多发性骨髓瘤（MM）细胞自噬与组蛋白甲基化及乙酰化修饰关系密切。我们发现MM特别是复发/难治者EZH2高表达，靶向抑制EZH2后MM细胞自噬活化并导致细胞死亡，同时hMOF/H4K16ac水平降低以抑制自噬相关基因表达。为此我们设想靶向EZH2诱发MM细胞自噬过程中，涉及EZH2/H3K27me3与hMOF/H4K16ac交互调控网络，并存在自噬反馈环路决定细胞命运，破坏其环路平衡有可能诱发MM死亡并克服耐药。本课题拟以MM患者、细胞系和小鼠荷瘤模型为研究对象，探讨基于靶向EZH2诱发MM细胞自噬反应模型中EZH2对hMOF直接调控机制和自噬反馈性调控hMOF通路的具体机制。明确H3K27me3与H4K16ac交互调控网络共同决定MM细胞命运，靶向EZH2通路可诱发MM细胞自噬及其他毒性效应的具体机制，为研发新的MM治疗策略提供理论依据。

Aberrance of histone modifications and disturbance of autophagic regulation may contribute to tumorigenesis. Autophagy of multiple myeloma cells is closely correlated with histone methylation and acetylation. High levels of EZH2 expression can be detected in patients with multiple myeloma, especially in patients with relapsed or refractory multiple myeloma. Inhibition of EZH2 can facilitate autophagy, induce cell death and reduce hMOF/H4K16ac level which aims to inhibit autophagy-related gene expression in multiple myeloma cells. Besides, expression of autophagy-related genes can be suppressed by the decrease of hMOF/H4K16ac. Based upon the above analysis, we have conceived that there exists “crosstalk” between EZH2/H3K27me3 and hMOF/H4K16ac during the induction of MM cell autophagy by targeting EZH2, thus constituting a feedback loop to regulate autophagy and determine the destiny of MM cell. Interrupting this feedback loop may induce MM cell death and overcome drug resistance. We will take MM patients, cell lines and xenograft mouse models as the objects to explore how EZH2 directly regulates hMOF and autophagy feedback loop inhibits hMOF pathway. We will clarify the specific mechanism that H3K27me3 and H4K16ac interact to determine the fate of MM cells，and that targeting EZH2 pathway can induce MM autophagy and other toxic effects.These studies will provide theoretical basis for the development of new MM treatment strategies.