Shen Jie, Zeng Zhi Hui, Yang Lei, Zeng Mao Jun, Ouyang Zhe Shen, Zhao Ming Yi, Yang Ming Hua
Department of Pediatrics,the Third Xiangya Hospital of Central South University,Changsha 410013,China.
Medical College of Hunan Normal University,Changsha 410000,China.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2019 Aug 30;41(4):548-555. doi: 10.3881/j.issn.1000-503X.10806.
Leukemia is a disease featured by the malignant proliferation of hematopoietic stem cells or progenitor cells in the blood system.While chemotherapy remains its mainstream treatment,disease relapse and drug resistance are still challenging problems.As one of the epigenetic mechanisms,histone methylation is involved in cell proliferation,differentiation,and apoptosis by regulating gene transcription.Recent studies have found that the histone demethylase lysine-specific demethylase 6A(KDM6A),also known as ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),is closely related to the occurrence of a variety of tumors,especially leukemia.KDM6A activates gene expression by demethylating H3K27me3 to H3K27me2 or H3K27me1.Besides,KDM6A can regulate the activation of the target gene transcription through its non-demethylase functions.It can serve as the subunit of complex of proteins associated with Set1,thus getting involved in the regulation of H3K4me1.It can be combined with yeast mating type conversion/sucrose unfermented complex family to promote the formation of an open chromatin conformation.Finally,it can promote the production of H3K27ac.This article reviews the recent studies on the structure and biological activity of histone demethylase KDM6A(UTX)and its role in treating leukemia,thus providing a new research direction for targeted treatment of leukemia.
白血病是一种以血液系统中造血干细胞或祖细胞恶性增殖为特征的疾病。虽然化疗仍然是其主要治疗方法，但疾病复发和耐药性仍然是具有挑战性的问题。作为表观遗传机制之一，组蛋白甲基化通过调节基因转录参与细胞增殖、分化和凋亡。最近的研究发现，组蛋白去甲基化酶赖氨酸特异性去甲基化酶6A（KDM6A），也称为X染色体上普遍转录的四肽重复序列（UTX），与多种肿瘤尤其是白血病的发生密切相关。KDM6A通过将H3K27me3去甲基化为H3K27me2或H3K27me1来激活基因表达。此外，KDM6A可以通过其非去甲基化功能调节靶基因转录的激活。它可以作为与Set1相关的蛋白质复合物的亚基，从而参与H3K4me1的调节。它可以与酵母交配型转换/蔗糖不发酵复合物家族结合，促进开放染色质构象的形成。最后，它可以促进H3K27ac的产生。本文综述了关于组蛋白去甲基化酶KDM6A（UTX）的结构和生物学活性及其在白血病治疗中的作用的最新研究，从而为白血病的靶向治疗提供了新的研究方向。
