Abstract：
Epigenetic modifiers are upregulated during the process of prostate cancer, acquiring resistance to castration therapy and becoming lethal metastatic castration-resistant prostate cancer (CRPC). However, the relationship between regulation of histone modifications and chromatin structure in CRPC has yet not fully been validated. Here, we reanalyzed publicly available clinical transcriptome and clinical outcome data and identified NSD2, a histone methyltransferase that catalyzes H3K36me2, as an epigenetic modifier that was upregulated in CRPC and whose increased expression in prostate cancer correlated with higher recurrence rate. We performed ChIP-seq, RNA-seq, and Hi-C to conduct comprehensive epigenomic and transcriptomic analyses to identify epigenetic reprogramming in CRPC. In regions where H3K36me2 was increased, H3K27me3 was decreased, and the compartment was shifted from inactive to active. In these regions, 68 aberrantly activated genes were identified as candidate downstream genes of NSD2 in CRPC. Among these genes, we identified KIF18A as critical for CRPC growth. Under NSD2 upregulation in CRPC, epigenetic alteration with H3K36me2-gain and H3K27me3-loss occurs accompanying with an inactive-to-active compartment shift, suggesting that histone modification and chromatin structure cooperatively change prostate carcinogenesis.
摘要：
表观遗传修饰剂在前列腺癌的过程中上调，获得对去势疗法的抵抗并成为致命的转移性去势抵抗前列腺癌（CRPC）。然而,CRPC中组蛋白修饰的调控与染色质结构之间的关系尚未得到充分验证.这里,我们重新分析了公开的临床转录组和临床结局数据,并确定NSD2是一种催化H3K36me2的组蛋白甲基转移酶,在CRPC中表达上调,其在前列腺癌中的表达增加与较高的复发率相关.我们执行了ChIP-seq,RNA-seq,和Hi-C进行全面的表观基因组和转录组学分析，以确定CRPC中的表观遗传重编程。在H3K36me2增加的地区，H3K27me3下降，隔室从非活动转变为活动。在这些地区,68个异常激活基因被鉴定为CRPC中NSD2的候选下游基因。在这些基因中,我们确定KIF18A对CRPC增长至关重要。在CRPC的NSD2上调下，H3K36me2增益和H3K27me3损失的表观遗传改变伴随着非活性到活性的区室转变。提示组蛋白修饰和染色质结构共同改变前列腺癌的发生。
