化疗抵抗是导致胶质瘤难治性的重要原因。申请人前期研究发现:组蛋白脱乙酰化酶6(HDAC6)可负调控缬酪肽包含蛋白(p97)降解，增强保护性自噬，导致耐药性的产生；抑制HDAC6可逆转这一过程，提示HDAC6-p97的负调控是逆转胶质瘤细胞耐药的潜在靶点，但是具体分子机制仍不明确。文献报道与前期研究证明:E3泛素连接酶TRIM50作为HDAC6的底物蛋白，其表达水平和乙酰化程度与p97降解有着紧密的联系。我们推测:HDAC6可能通过乙酰化修饰，调控TRIM50多聚泛素化过程的募集，从而介导p97通过自噬途径降解。本项目拟从原代胶质瘤细胞、细胞耐药模型和裸鼠原位肿瘤移植模型三个层面，通过基因敲除和过表达，功能结构域活性突变，激光共聚焦和免疫共沉淀等实验，研究TRIM50介导HDAC6负调控p97抑制保护性自噬的分子机制，从而为逆转胶质瘤化疗抵抗提供新的思路和分子靶点。

Malignant gliomas remains incurable brain tumors because of gliomachemoresistance. We have recently shown that histone deacetylase 6 (HDAC6) can negatively regulate valosin containing protein (p97), so as to enhance autophagy, reduce ubiquitin degradation, promote endoplasmic reticulum stress tolerance, leading to the emergence of drug resistance. It is suggested that the negative regulation of HDAC6-p97 is a potential target for reversing the drug resistance of glioma cells, but the specific mechanism is still not clear. Further studies show that the expression and the acetylation of the E3 ubiquitin ligase TRIM50 which is a substrate of HDAC6 protein play important roles in the degradation of p97. Therefore, we hypothesized that HDAC6 may regulate the ubiquitination of TRIM50 by acetylation, which can mediate the autophagy-dependent degradation of p97. The aim of this study is to investigate molecular mechanism of regulation of HDAC6-p97 and the autophagy-ubiquitin pathway mediated by TRIM50 via establishment of TRIM50 gene overexpress or knockout models including primary glioma cells, drug resistance cell lines, nude mouse orthotopic transplantation. The results might provide new ideas and molecular targets for reversing the resistance of glioma.