Mechanistic insights into KDM4A driven genomic instability

Abstract

Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these marks on chromatin and their effects on transcription and proliferation, it naturally follows that demethylation serves an equally important role in these cellular processes. In this review, we highlight the role of KDM4A in transcriptional modulation, either dependent or independent of its enzymatic activity, arising from the amplification of this demethylase in cancer. KDM4A modulates re-replication of distinct genomic loci, activates cell cycle inducers, and represses proteins involved in checkpoint control giving rise to proliferative damage, mitotic disturbances and chromosomal breaks, ultimately resulting in genomic instability. In parallel, emerging evidence of non-nuclear substrates of epigenetic modulators emphasize the need to investigate the role of KDM4A in regulating non-nuclear substrates and evaluate their contribution to genomic instability in this context. The existence of promising KDM-specific inhibitors makes these demethylases an attractive target for therapeutic intervention in cancers.

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

“…KDM4A is either deleted or overexpressed (predominantly through gene amplification) in several types of cancer including lung, breast, ovarian, and head and neck cancer [ 11 , 20 , 133 ]. KDM4A promotes S-phase progression and regulates replication timing [ 19 , 20 ] and its function in cancer is best understood in the context of its overexpression (for a detailed review please see [ 107 , 214 ]. Interestingly, KDM4A overexpression results in the (extrachromosomal) amplification of chromosome 1q12, through site-specific re-replication during a single cell cycle, and 1q12 amplification also correlates with KDM4A overexpression in tumor samples [ 20 ].…”

Cis-Regulatory Atlas in Primary Human CD4+ T Cells

“…KDM4A demethylated both H3K36me3(57) and H3K9me3, and recruits NCOR (nuclear core repressor). (58) Other canonical repressors were also enriched in NREs, including members of polycomb repressor complex 1 (RNF2, RYBP) and polycomb repressor complex 2 (EZH2, SUZ12, EED). Another candidate for NRE function in CD4+ T cells is the known repressor PBXIP1 [(HPIP)], which inhibited PBX1 homeobox target activation(59) and is highly expressed in CD4+ T cells.…”

SUMO Modification of Histone Demethylase KDM4A in Kaposi’s Sarcoma-Associated Herpesvirus-Induced Primary Effusion Lymphoma

“…Therefore, the SUMO-deficient mutant of KDM4A (KDM4A-K471R) cannot rescue the virus lytic gene expression and virion production in KDM4A knockdown BCBL-1 cells ( 25 ). Together with the long-acknowledged oncogenic role of KDM4A in inhibiting apoptosis ( 28 , 29 ), we hypothesize that targeting KDM4A or its SUMO modification may reduce infectious viral particle production, prevent viral antiapoptotic effects, and be a potential therapeutic option to kill PEL cells.…”