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

Epigenetic alterations along with genetic mutation are thought to represent one of the major driving forces of cancer initiation and progression.Histone demethylases play important roles in gene transcription regulation,DNA replication and damage repair,cell metabolism programming,and embryo development by removing methyl groups from the lysine or arginine residues of histone tails.The histone demethylase KDM4 B is able to demethylate H3K9me2/me3,and is frequently overexpressed in various cancer types.Previous studies have indicated that KDM4 B can regulate the expression of proto-oncogenes or tumor suppressor genes,and affect the DNA repair efficacy.A systematic analysis of the changes of genome-wide H3K9me3 level caused by KDM4 B overexpression has not been reported,which brings difficulties to thoroughly understanding the molecular mechanism underlying the KDM4 B overexpression in cancer progress.In this study,we systemically analyzed the whole-genome H3K9me3 distribution in tumour cells by Ch IP-seq,and found that H3K9me3 was largely enriched in the repeat sequence named long interspersed nuclear element-1(LINE-1).Notably,a significant proportion of KDM4B-dependent H3K9me3 was located in evolutionarily young LINE-1 elements,which likely retain retrotransposition activity.Consistently,ectopic wilde type(WT)KDM4B rather than the catalytic dead mutant promoted LINE-1 expression,while KDM4 B depletion reduced it.Furthermore,KDM4 B overexpression clearly enhanced LINE-1 retrotransposition efficacy,copy number and associated DNA damage,presumably via the KDM4 B histone demethylating ability.Moreover,breast cancer cell lines bearing a higher KDM4 B level also exhibited increased LINE-1 expression?copy number and retrotransposition activity compared with other cell lines.Importantly,pharmacological inhibition of KDM4 B significantly reduced LINE-1 expression and DNA damage in breast cancer cells with excessive KDM4 B.To investigate the molecular mechanism by which KDM4 B alters histone methylation,we preliminarily examined the interactions between the chromatin-associated functional domains of KDM4 B and the oligopeptides containing various type of tri-methylation modification.Our study identified that KDM4 B as a novel LINE-1 regulator plays an important role in genome instability,revealing a novel etiology of KDM4 B overexpression in tumorigenesis and the new origin of cancer cell genome instability,providing clues for the development of new cancer prevention strategies and therapies.