KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells

Abstract

Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ~130 kDa proteins (KDM4A–C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity. Various studies have shown that KDM4A/JMJD2A, KDM4B/JMJD2B and/or KDM4C/JMJD2C are overexpressed in breast, colorectal, lung, prostate and other tumors and are required for efficient cancer cell growth. In part, this may be due to their ability to modulate transcription factors such as the androgen and estrogen receptor. Thus, KDM4 proteins present themselves as novel potential drug targets. Accordingly, multiple attempts are underway to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases.

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

“…The role of Jumonji domain-containing protein 2A (JMJD2A), which targets methylated H3K36me3 and prevents senescence by modulating p53 and Rb pathways, 60 has been well studied in cancer. 45 Its potential role in aging has also been described. 61 The presence of JMJD2A and RBBP5 in the absence of H3K36me3 in aDMRs hypermethylated with age suggests activity of p53 and Rb pathways at early developmental stages and their silencing followed by increased methylation over time.…”

“…Several epigenomic marks were identified as differentially enriched, that is, significantly enriched in positive aDMRs and aGENs while depleted in negative aDMRs and aGENs, or vice versa. Among them were repressor EZH2, histone deacetylase HDAC2, lysine-specific demethylase JMJD2A (aka KDM4A), 45 and a component of methyltransferase complex, RBBP5 46 (Table S6). These results highlight clear differences in histone code and histone modifiers associated with positive and negative aDMRs.…”

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

“…The histone demethylase JMJD2C (KMD4C, GASC1) can demethylate trimethylated H3K9 (H3K9me3) and H3K36 (H3K36me3). 68,69 Previously known as GASC1, this histone demethylase found amplified in esophageal SCC. 70,71 Moreover, knockdown of KDM4C caused decreased proliferation of the tumor cells.…”

KDM4D crosstalks with PARP1 and RNA at DNA DSBs

“…KDM4A-D proteins function in several cellular processes, including DNA replication, differentiation and gene expression regulation. 3 Recently, KDM4D was demonstrated to act in the DDR and modulate DSB repair. 4,5 KDM4D depletion impairs the chromatin association of the master protein kinase, ATM.…”

“…5 This difference may result of dissimilar structure and substrate specificity between the 2 demethylases. 3 The recruitment of several DDR proteins to DNA damage sites is mediated by different key DDR proteins, such as ATM and PARP1. 1 Noteworthy, KDM4D recruitment is independent of ATM activity but is PARP1-dependent.…”