HDAC3通过调节脂质生成-糖酵解途径影响胶质母细胞瘤生长的机制研究

胶质母细胞瘤（GBM）中肿瘤细胞在遗传突变和表观遗传变化驱使下进行代谢重编程，以经济高效为原则满足肿瘤生长所需，物质能量过度匮乏或积累都会影响肿瘤进程，深入理解GBM代谢调控机理对肿瘤治疗有积极意义。已报道HDAC3参与多种组织的脂质调控，而我们观察到GBM患者和小鼠样本中都有HDAC3的高表达，并与较差预后相关；敲除Hdac3可显著延长小鼠生存期，伴随着肿瘤细胞中脂质积累和脂滴异常增多，以及糖酵解水平的降低。基于前期实验我们推测HDAC3缺失通过去除对SREBP2的抑制作用过度激活脂质生成，而异常积累的脂滴可结合糖代谢调控因子MLXIP和MLX影响其入核转录激活，从而干扰糖酵解抑制肿瘤生长。本项目将结合小鼠模型和临床样本，借助CUT&Tag、RNAseq、代谢组学等技术，详细阐述HDAC3在GBM中对脂质稳态的特异性调控和通过脂滴影响糖酵解的机制，为靶向胶质瘤代谢的联合治疗提供理论依据。

Glioblastoma (GBM), the most common primary malignant brain tumor, remains uniformly fatal despite aggressive therapies. To adapt to rapid proliferation and invasion, GBM cells undergo metabolic reprogramming, which not only provides the various essential cellular components and energy required for growth, but also plays an important role in the resistance of radio- and chemo-therapy. Therefore, it is great helpful to discover the underlying mechanism and potential targets involving in metabolic alterations. HDAC3 has been reported to participate in lipid metabolism and homoeostasis in certain tissues, here, we found that both patients and mouse GBM models have high expression of HDAC3, which also correlated to poor prognosis; Hdac3 deletion can significantly prolong the mouse survival, accompanied with lipid and droplets accumulation, as well as the decreased glycolysis level. Based on previous reports and our experiments, we propose that HDAC3 inhibition can overactivate lipogenesis through the de-repression of SREBP2; when lipid droplets accumulation, MLXIP and MLX, the transcription factors in regulating glucose metabolism, bind to lipid droplets reducing their availability for transcriptional activity in glycolysis. In this project, with GBM mouse models and clinical samples, we set out to disclose the mechanism of HDAC3 modulation on glucose and lipid metabolism in glioblastoma, bringing new insights in combinational treatment targeting metabolism for GBM therapies.