上皮间质转化（EMT）是胶质母细胞瘤（GBM）放化疗抵抗的重要原因，我们已发现下调TPD52L2可激活Wnt通路，促进GBM的EMT并介导放化疗抵抗。进一步研究显示替莫唑胺（TMZ）诱导下，RBBP4及组蛋白H3K9me3表达上调，而去乙酰化酶HDAC6及TPD52L2表达下调，同时RBBP4 K4位点乙酰化增加。HDACi抑制HDAC6可干扰RBBP4的泛素化降解，促进组蛋白H3K9me3修饰，生信分析提示RBBP4为HDAC6的潜在靶蛋白，且可影响c-Myc与TPD52L2启动子结合。综上推测：TMZ诱导HDAC6下调，促进RBBP4的K4位点乙酰化并抑制其泛素化降解，进而增加H3K9me3修饰，抑制c-Myc与TPD52L2启动子结合，激活TPD52L2/Wnt/β-catenin信号轴促进EMT及TMZ治疗抵抗。本课题拟探明以上具体机制，以期为GBM放化疗治疗增敏提供新的靶点。

Epithelial-mesenchymal transition (EMT) is the most important factor for migration, invasion and resistance to radiotherapy and chemotherapy of glioblastoma (GBM). Our preliminary work proved that Tumor protein D52 like 2 (TPD52L2) mediated EMT process by up-regulating Wnt/β-catenin pathway，and promoted the resistance to radiotherapy and chemotherapy. In this study GBM cells was treated with Temozolomide (TMZ), we found that the Retinoblastoma binding protein 4 (RBBP4) and H3K9me3 level were upregulated, and the downregulation of histone deacetylase HDAC6 and TPD52L2 level, which accompanied with the upregulation of RBBP4 K4 site acetylation. Inhibiting the function of HDAC6 by HDACi interfered the ubiquitination of RBBP4 and inhibited its degradation, and promoted histone H3K9me3 modification. Further detection revealed that RBBP4 may be the target protein of HDAC6, and RBBP4 may regulate the binding of c-Myc with TPD52L2 promoter. So we proposed the hypothesis that HDAC6 was down-regulated by TMZ, resulting in the increase of K4 acetylation level and the decrease of ubiquitination of RBBP4, which inhibited the degradation of RBBP4. Further the RBBP4 remodel chromatin structure on the TPD52L2 promoter by regulating H3K9me3 level, and down-regulated TPD52L2 expression by inhibiting the binding of c-Myc with TPD52L2 promoter, the Wnt/β-catenin pathway was activated，and promoted EMT and resistance to radiotherapy combined with TMZ chemotherapy. This research took the aim to investigate and prove the above molecular mechanism in details, and was hoping to provide the experimental evidence and molecular-based therapeutic targets for GBM chemoradiotherapy resistant.