Abstract
The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A. Pathway enrichment analysis of cells with KDM3A knockdown prioritized androgen signaling indicating that KDM3A plays a key role in regulating androgen receptor activity. Matched ChIP-Seq and knockdown experiments of KDM3A in combination with ChIP-Seq of the androgen receptor resulted in a gain of H3K9 methylation marks around androgen receptor binding sites of selected transcriptional targets in androgen signaling including positive regulation of KRT19, NKX3-1, KLK3, NDRG1, MAF, CREB3L4, MYC, INPP4B, PTK2B, MAPK1, MAP2K1, IGF1, E2F1, HSP90AA1, HIF1A, and ACSL3. The cancer systems biology analysis of KDM3A-dependent genes identifies an epigenetic and transcriptional network in androgen response, hypoxia, glycolysis, and lipid metabolism. Genome-wide ChIP-Seq data highlights specific gene targets and the ability of epigenetic master regulators to control oncogenic pathways and cancer progression.
Highlights
Methylation of histone lysine residues is a significant component of epigenetics and is associated with control of gene expression [1]
KDM events were functionally annotated by mapping bound regions to the human genome and by classifying them according to the nearest gene locus and relative position within coding regions
Promoter or transcription start sites (TSS) and transcription termination sites (TTS) genomic annotations are defined as being within ± 1000 bp of the gene-coding body
Summary
Methylation of histone lysine residues is a significant component of epigenetics and is associated with control of gene expression [1]. Methylation of lysine 9 of histone H3 (H3K9) has been recognized as hallmark of transcriptionally suppressed genes [2]. In prostate adenocarcinoma (PRAD), KDM3A www.impactjournals.com/oncotarget functions as a transcriptional coactivator for the androgen receptor (AR; Gene ID: 367) [3, 9]. The ability to cooperate with the AR highlights a potential role of KDM3A as coactivator and driving force for sex-specific tissue development as well as for prostate cancer initiation and progression. The activated AR dimer binds to androgen response elements (AREs) present in the promoter or enhancer of AR-regulated target genes and recruits coactivators or co-repressors to regulate gene expression [13]. In addition to the AR, KDM3A has been found to regulate expression and/or activity of several transcription factors such as PPARG, KLF2, ESR1, and HOXA1 [14,15,16,17]
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