EZH2/miR-101正反馈环路通过调控ATRX影响GBM对TMZ化疗敏感性的机制研究

胶质母细胞瘤（GBM）是颅内最常见的恶性肿瘤，替莫唑胺（TMZ）作为GBM的一线化疗药物，极易产生耐药，克服GBM对TMZ的耐药是临床治疗的关键。本研究前期发现EZH2在GBM组织及耐药细胞中高表达与TMZ敏感性相关，且EZH2通过调控H3K27me3与miR-101之间形成正反馈环路，导致DNA修复蛋白ATRX的表达增强。而沉默EZH2后可明显升高miR-101的表达，进一步降低EZH2和ATRX的活性，从而介导GBM细胞对TMZ化疗的敏感性。因此，推测EZH2/miR-101形成正反馈环路调控ATRX通过DNA修复机制影响GBM细胞对TMZ的敏感性。本研究旨在通过体内、外实验探讨靶向EZH2增强GBM细胞对TMZ敏感性的机制，评估靶向EZH2/miR-101正反馈环路，进而调控ATRX表达，提高GBM对TMZ化疗疗效的可行性，为靶向EZH2联合TMZ治疗GBM的临床转化提供实验依据。

Glioblastoma (GBM) is the most common intracranial malignant tumor. Temozolomide (TMZ), as the first-line chemotherapeutic drug for GBM, is prone to drug resistance. Overcoming the resistance of GBM to TMZ is the key to clinical treatment. In our study, it was found that the higher expression of EZH2 in GBM tissues and drug-resistant cells is associated with TMZ sensitivity. EZH2 could regulate H3K27me3 and form a positive feedback loop with miR-101, resulting in increased expression of the DNA repair protein ATRX. The silencing of EZH2 could significantly increase the expression of miR-101 and further reduce the activity of EZH2 and ATRX, thereby mediating the sensitivity of GBM cells to TMZ chemotherapy. Therefore, it is presumed that EZH2/miR-101 forms a positive feedback loop to regulate ATRX and through DNA repair process to affect the sensitivity of GBM cells to TMZ. In the present study, the mechanism of targeting EZH2 to enhance the sensitivity of GBM cells to TMZ through in vivo and in vitro experiments will be investigated, and to evaluate the positive feedback loop of targeting EZH2/miR-101, thereby regulating ATRX expression and improving the feasibility of GBM for TMZ chemotherapy .To provide experimental evidence for the clinical transformation of targeted EZH2 combined with TMZ in the treatment of GBM.