Histone Demethylase KDM4B Promotes DNA Damage by Activating Long Interspersed Nuclear Element-1
文献类型： 外文期刊
作者： Xiang, Ying 1 ; Yan, Kai 2 ; Zheng, Qian 1 ; Ke, Haiqiang 1 ; Cheng, Jie 1 ; Xiong, Wenjun 1 ; Shi, Xin 1 ; Wei, Lei 1 ; Zha 1 ;
作者机构： 1.Wuhan Univ, Sch Basic Med Sci, Wuhan 430071, Hubei, Peoples R China
2.Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China
3.Hubei Prov Key Lab Developmentally Originated Dis, Wuhan, Hubei, Peoples R China
4.Hubei Prov Key Lab Allergy & Immunol, Wuhan, Hubei, Peoples R China
5.Yangtze Univ, Dept Cell Biol & Genet, Jingzhou, Hubei, Peoples R China
6.Huanggang Cent Hosp, Dept Oncol, Huanggang, Hubei, Peoples R China
7.Chinese Acad Fishery Sci, Yangtze River Fisheries Res Inst, Key Lab Freshwater Biodivers Conservat & Utilizat, Minist Agr, Wuhan, Hubei, Peoples R China
8.Guangdong Key Lab Genome Stabil & Human Dis Preve, Dept Pharmacol, Shenzhen, Guangdong, Peoples R China
9.Shenzhen Univ, Int Canc Ctr, Sch Med, Shenzhen, Guangdong, Peoples R China
10.Univ Chinese Acad Sci, Beijing, Peoples R China
11.Chinese Acad Sci, Cter Excellence Anim Evolut & Genet, Kunming, Yunnan, Peoples R China
期刊名称：CANCER RESEARCH （ 影响因子：12.701； 五年影响因子：12.843 ）
ISSN： 0008-5472
年卷期： 2019 年 79 卷 1 期
页码：
收录情况： SCI
摘要： The histone demethylase KDM4B is frequently overexpressed in various cancer types, and previous studies have indicated that the primary oncogenic function of KDM4B is its ability to demethylate H3K9me3 in different tumors, resulting in altered gene expression and genome instability. A genome-wide analysis to evaluate the effect of KDM4B on the global or local H3K9me3 level has not been performed. In this study, we assess whole-genome H3K9me3 distribution in cancer cells and find that H3K9me3 is largely enriched in long interspersed nuclear element-1 (LINE-1). A significant proportion of KDM4B-dependent H3K9me3 was located in evolutionarily young LINE-1 elements, which likely retain retrotransposition activity. Ectopic expression of KDM4B promoted LINE-1 expression, while depletion of KDM4B reduced it. Furthermore, KDM4B overexpression enhanced LINE-1 retrotransposition efficacy, copy number, and associated DNA damage, presumably via the histone demethylase activity of KDM4B. Breast cancer cell lines expressing high levels of KDM4B also exhibited increased LINE-1 expression and copy number compared with other cell lines. Pharmacologic inhibition of KDM4B significantly reduced LINE-1 expression and DNA damage in breast cancer cells with excessive KDM4B. Our study not only identifies KDM4B as a novel regulator of LINE-1, but it also suggests an unexpected oncogenic role for KDM4B overexpression in tumorigenesis, providing clues for the development of new cancer prevention strategies and therapies. Significance: The histone demethylase KDM4B promotes tumorigenesis by inducing retrotransposition and DNA damage.
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