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 , 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 as critical for CRPC growth. Under 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.

中文翻译：

---

H3K36me2 染色质激活和转移性去势抵抗性前列腺癌中的区室移位

表观遗传修饰物在前列腺癌的过程中上调，获得对去势治疗的抵抗并成为致命的转移性去势抵抗性前列腺癌（CRPC）。然而，CRPC 中组蛋白修饰调控与染色质结构之间的关系尚未得到充分验证。在这里，我们重新分析了公开的临床转录组和临床结果数据，并确定了一种催化 H3K36me2 的组蛋白甲基转移酶，作为一种表观遗传修饰剂，在 CRPC 中上调，并且其在前列腺癌中表达的增加与较高的复发率相关。我们进行了 ChIP-seq、RNA-seq 和 Hi-C 来进行全面的表观基因组和转录组分析，以确定 CRPC 中的表观遗传重编程。在 H3K36me2 增加的区域，H3K27me3 减少，隔室从不活跃转变为活跃。在这些区域中，68 个异常激活的基因被鉴定为 CRPC 中 NSD2 的候选下游基因。在这些基因中，我们确定对 CRPC 生长至关重要。在 CRPC 上调下，H3K36me2 增加和 H3K27me3 丢失的表观遗传改变伴随着非活性到活性区室的转变，表明组蛋白修饰和染色质结构协同改变前列腺癌发生。