E2F6抑制USP11组蛋白去泛素化作用在GBM对TMZ耐药的机制研究

胶质母细胞瘤（GBM）对替莫唑胺（TMZ）耐药是肿瘤预后不良的主要原因之一。申请人前期使用CRISPR-Cas9基因编辑筛选文库筛选出E2F6是GBM对TMZ的耐药基因，并发现E2F6参与DNA损伤修复调控。然而，E2F6作为TMZ的耐药基因的具体机制尚不明确。本研究为揭示“E2F6抑制USP11组蛋白去泛素化在GBM对TMZ耐药的机制研究”，以多个细胞系和临床标本为研究对象，1、研究E2F6抑制USP11转录调控；2、研究USP11参与H2AK13ub的去泛素化机制；3、H2AK13ub募集53BP1从而开启对TMZ诱导的DNA损伤的非同源末端连接修复；4、敲除E2F6和增加USP11表达增加TMZ治疗的敏感性。为探索GBM对TMZ耐药治疗向临床应用转化提供理论基础和研究手段。

One of the main causes of poor prognosis of glioblastoma (GBM) patients is its resistance to temozolomide (TMZ). We previously used the CRISPR-Cas9 gene editing screening library to select E2F6 as a resistance gene of GBM to TMZ, and found that E2F6 is involved in the regulation of DNA damage repair. However, the specific mechanism of E2F6 as a TMZ resistance gene is not yet clear. In this study, we aimed to reveal the mechanism of GBM resistance to TMZ that E2F6 inhibits histone deubiquitination by USP11. We use multiple cell lines and clinical specimens as the research object to study: 1. Inhibition of USP11 transcription by E2F6; 2. Deubiquitination mechanism of H2AK13ub by USP11; 3. H2AK13ub recruited 53BP1 to initiate the non-homologous end junctions to TMZ-induced DNA damage; 4. Knockout of E2F6 and increased expression of USP11 may enhance the sensitivity of TMZ treatment. It provides theoretical basis and research methods for exploring the clinical application of GBM treatment to TMZ.