Wilson Stephen, Fan Lingling, Sahgal Natasha, Qi Jianfei, Filipp Fabian V
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, CA 95343, USA.
Department of Biochemistry and Molecular Biology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Oncotarget. 2017 May 2;8(18):30328-30343. doi: 10.18632/oncotarget.15681.
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.
赖氨酸去甲基化酶3A(KDM3A、JMJD1A或JHDM2A)在多种生物学过程中控制转录网络,如精子发生、新陈代谢、干细胞活性和肿瘤进展。我们匹配了转录组和ChIP-Seq图谱,以破译KDM3A在前列腺癌细胞中对表观遗传控制的全基因组调控网络。监测组蛋白3赖氨酸9(H3K9)甲基化标记的ChIP-Seq实验显示了KDM3A的全局组蛋白去甲基化作用。对组蛋白去甲基化事件和基因表达变化的综合评估表明存在主要的转录激活,这表明不同的致癌调节因子可能与KDM3A的表观遗传模式协同作用。对KDM3A敲低的细胞进行通路富集分析,结果显示雄激素信号通路优先,这表明KDM3A在调节雄激素受体活性中起关键作用。KDM3A的匹配ChIP-Seq和敲低实验与雄激素受体的ChIP-Seq相结合,导致在雄激素信号通路中选定转录靶点的雄激素受体结合位点周围H3K9甲基化标记增加,包括对KRT19、NKX3-1、KLK3、NDRG1、MAF、CREB3L4、MYC、INPP4B、PTK2B、MAPK1、MAP2K1、IGF1、E2F1、HSP90AA1、HIF1A和ACSL3的正向调节。对KDM3A依赖性基因的癌症系统生物学分析确定了雄激素应答、缺氧、糖酵解和脂质代谢中的表观遗传和转录网络。全基因组ChIP-Seq数据突出了特定的基因靶点以及表观遗传主调节因子控制致癌途径和癌症进展的能力。