Teng Xinqi, Wang Yiming, Qu Qiang, Xu Weixin, Zhuang Haihui, Wei Yiwen, Dai Yinghuan, Qu Jian
Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan, China.
Department of Pharmacy, Wuhan No.1 Hospital (Wuhan Integrated TCM & Western Medicine Hospital), Wuhan 430022, Hubei, China.
Cancer Drug Resist. 2025 Jul 22;8:37. doi: 10.20517/cdr.2025.105. eCollection 2025.
Glioblastoma (GBM) is the most malignant grade of glioma, characterized by high recurrence, poor prognosis, and frequent chemoresistance. There is an urgent need for alternative treatment strategies. In this study, we evaluated the effects of THZ2, a covalent inhibitor targeting the super-enhancer (SE) component CDK7, on GBM growth and chemoresistance. We also used another SE inhibitor, JQ1, to further validate the inhibitory effects of targeting SEs in GBM, thereby providing new treatment strategies for patients. A variety of and assays were performed to explore the anti-GBM effects of SE inhibitors. We assessed the effects of SE inhibitors in combination with temozolomide (TMZ) on GBM cells and calculated the combination index. Additionally, CUT&RUN assays were conducted to examine protein-DNA interactions. THZ2 inhibited the proliferation, migration, and invasion of GBM cells and induced cell cycle arrest and apoptosis. Furthermore, both THZ2 and JQ1 exhibited synergistic antitumor effects when combined with TMZ in GBM cells. Notably, THZ2 reversed TMZ resistance in GBM cells by suppressing the expression of the SE-associated gene . We also found that , , and interact with histone H3K27ac. Our findings demonstrate that SE inhibitors exert antitumor effects in GBM and act synergistically with TMZ. THZ2 may enhance chemosensitivity by downregulating the SE-related gene , and it holds promise as a novel therapeutic agent for GBM patients.
胶质母细胞瘤（GBM）是胶质瘤中恶性程度最高的类型，具有高复发率、预后差和频繁的化疗耐药性等特点。迫切需要替代治疗策略。在本研究中，我们评估了靶向超级增强子（SE）成分CDK7的共价抑制剂THZ2对GBM生长和化疗耐药性的影响。我们还使用了另一种SE抑制剂JQ1来进一步验证靶向SEs对GBM的抑制作用，从而为患者提供新的治疗策略。进行了各种实验来探索SE抑制剂的抗GBM作用。我们评估了SE抑制剂与替莫唑胺（TMZ）联合对GBM细胞的影响，并计算了联合指数。此外，进行了切割与运行（CUT&RUN）实验以检测蛋白质 - DNA相互作用。THZ2抑制了GBM细胞的增殖、迁移和侵袭，并诱导细胞周期停滞和凋亡。此外，THZ2和JQ1与TMZ联合使用时在GBM细胞中均表现出协同抗肿瘤作用。值得注意的是，THZ2通过抑制SE相关基因的表达逆转了GBM细胞中的TMZ耐药性。我们还发现，[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]与组蛋白H3K27ac相互作用。我们的研究结果表明，SE抑制剂在GBM中发挥抗肿瘤作用，并与TMZ协同作用。THZ2可能通过下调SE相关基因增强化疗敏感性，有望成为GBM患者的新型治疗药物。
