The histone demethylase KDM3A regulates the transcriptional program of the androgen receptor in prostate cancer cells

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 KDM3A to control oncogenic pathways in prostate cancer cells.

赖氨酸去甲基化酶3A（lysine demethylase 3A，简称KDM3A，又称JMJD1A或JHDM2A）可调控多种生物学过程中的转录网络，涵盖精子发生、代谢、干细胞活性及肿瘤进展等环节。本研究通过匹配转录组学（transcriptomic）图谱与染色质免疫共沉淀测序（ChIP-Seq）数据，解析了KDM3A在前列腺癌细胞中介导的表观遗传全基因组调控网络。针对组蛋白3赖氨酸9（H3K9）甲基化标记的ChIP-Seq实验结果显示，KDM3A具有全局性的组蛋白去甲基化效应。联合分析组蛋白去甲基化事件与基因表达变化后发现，主要呈现转录激活特征，提示不同致癌调控因子可与KDM3A介导的表观遗传模式协同发挥作用。对KDM3A敲低的细胞进行通路富集分析，结果显著富集于雄激素信号通路，表明KDM3A在调控雄激素受体活性中发挥关键作用。将KDM3A的ChIP-Seq实验、敲低实验与雄激素受体的ChIP-Seq数据相结合后发现，在雄激素信号通路的选定转录靶基因的雄激素受体结合位点周围，H3K9甲基化标记显著富集，且这些靶基因包括KRT19、NKX3-1、KLK3、NDRG1、MAF、CREB3L4、MYC、INPP4B、PTK2B、MAPK1、MAP2K1、IGF1、E2F1、HSP90AA1、HIF1A及ACSL3的正向调控基因。对KDM3A依赖型基因开展癌症系统生物学分析，鉴定出其在雄激素应答、缺氧、糖酵解及脂质代谢过程中的表观遗传与转录调控网络。全基因组ChIP-Seq数据进一步明确了KDM3A在前列腺癌细胞中的特异性基因靶标及其调控致癌通路的能力。