Histone Demethylase KDM4B Promotes DNA Damage by Activating Long Interspersed Nuclear Element-1

Abstract

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.

New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

“…LINE-1 retrotransposon silenced also through histone modifications. Histone demethylase KDM4B may enhance the LINE-1 retrotransposition efficacy, whereas depletion of KDM4B reduced it in breast cancer (Xiang et al, 2019). Elevated LINE-1 expression was found in PC9 drug-tolerant persister (DTP) cancer cells treated with the EGFR inhibitor erlotinib.…”

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

“…Histone demethylase 1 can physically interact with E3 ubiquitin ligase (RNF168) at the DNA damage site and then mediate the process of DNA damage repair (Duquette, Kim, Shi, & Berns, 2018). KDM4B is a histone demethylase that promotes DNA damage in 293T cells; its overexpression in MCF7 cells can aggravate DNA damage, and inhibition of KDM4B can reduce DNA damage (Xiang et al, 2019). To explore the role of JHDM2A in arsenic‐induced DNA damage, we up‐ or downregulated the expression of JHDM2A in arsenic‐exposed L‐02 cells.…”

Genomic Indexing by Somatic Gene Recombination of mRNA/ncRNA – Does It Play a Role in Genomic Mosaicism, Memory Formation, and Alzheimer’s Disease?

“…A recent study showed upregulation of the histone demethylase KDM4B in AD brains (Park et al, 2019). This histone demethylase had previously been identified to promote LINE-1 expression and enhance LINE-1 copy number and retrotransposition efficacy, while its depletion reduces LINE-1 expression (Xiang et al, 2019). In addition, SIRT6, a histone deacetylase and powerful repressor of L1-activity by ribosylating KAP1 (van Meter et al, 2014), a nuclear co-repressor protein of LINE-1 (Rowe et al, 2010;Castro-Diaz et al, 2014), is reduced in AD (Kaluski et al, 2017), which could further contribute to the activation of LINE-1.…”