The histone demethylaseKDM3Aregulates the transcriptional program of the androgen receptor in prostate cancer cells

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.

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

“…Moreover, the DEGs were found to be elevated in clinical metastatic PCa [47]. The expression of AR or its target genes were unaffected by shKDM3B treatment, thus demonstrating that KDM3B, in contrast to other KDM members, does not act via AR [11,18,37,62]. LNCaP cells were largely unaffected by KDM3B knockdown.…”

“…3a). Isoform-1 (1761 AA) is proposed to be the canonical form with a Jumonji-C (JmjC) domain, C2HC4 zinc-finger domain, serine-rich domain, and a LxxLL motif [36,37]. Isoform-2 is slightly shorter with a truncated N-terminus [38], while Isoform-3 lacks the first 1000 amino acids and does not contain the nuclear localization signal [38].…”

The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice

“…Methylation of histone lysine is important for epigeneticassociated gene expression profiles in cancer. 6,7 Histone methylation profiles have been demonstrated to be critical in developmental biology, neurological disorders, and numerous cancer types. [8][9][10] In addition, hypoxia modulates histone-modifying factor expression, leading to changes in histone marks.…”

“…Therefore, understanding how KDM3A specifically regulates gene expression is an area of current inquiry and is vital for understanding epigenetics in human disease. KDM3A activity is deregulated in several cancers, including prostate, 7,18 breast, 19 and Ewing sarcoma. 20,21 KDM3A regulates several transcription factors, such as PPARG, KLF2, ESR1, and HOXA1.…”

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

“…As well as modulating gene expression, this modification is involved in X-chromosome inactivation [3,4], DNA damage repair [5], and in the determination and differentiation of embryonic stem cells [6,7]. However, it is widely reported that dysregulation of HMT expression and activity is frequently observed in cancer [8][9][10][11]. Two main histone residues, arginine and lysine groups, are methylated by HMTs.…”