BRD4蛋白作为恶性胶质瘤治疗靶点的研究进展

Progress in BRD4 as a therapeutic target for malignant glioma

近年来研究表明,脑胶质瘤中广泛存在表观遗传学异常现象。与基因突变不同,表观遗传学是可逆的,它可以调控胶质瘤细胞致瘤和非致瘤状态间的转换。组蛋白乙酰化是一种重要的表观遗传学修饰方式。组蛋白乙酰化阅读器——布罗莫结构域蛋白4(bromodomain-containing protein 4,BRD4)作为胶质瘤治疗靶点,为恢复胶质瘤细胞正常的表观遗传学状态,更有效地治疗恶性胶质瘤提供了新的研究角度[1-3]。目前研究表明,下调BRD4基因或采用BRD4选择性抑制剂JQ1,能够有效地抑制胶质母细胞瘤干细胞(glioblastoma stem cells,GSCs)增殖,促进细胞凋亡,但作用效果有一定的局限性,这提示不能被JQ1抑制的胶质瘤细胞存在其它途径维持异常的自我更新,因此BRD4抑制剂与其它药物联用治疗脑胶质瘤可能具有广阔的前景。

Malignant glioma is a highly invasive and fatal tumor disease of central nervous system,for which a good therapeutic method is still not established.In recent years,studies have shown that epigenetic regulation is closely re‐lated to the occurrence and the development of malignant glioma.Bromodomain-containing protein 4(BRD4)is a epigene‐tic"reader"that play important roles in biological activities such as gene transcription and cell cycle regulation.This pa‐per summarizes the structure and biological function of BRD4,the progress in early clinical trials of BRD4 inhibitors,and the therapeutic effect of BRD4 inhibitors on malignant glioma.