Chromatin activation with H3K36me2 and compartment shift in metastatic castration-resistant prostate cancer

• Published in: Cancer letters 2024-04, Vol.588, p.216815-216815, Article 216815
• Main Authors: Kanaoka, Sanji, Okabe, Atsushi, Kanesaka, Manato, Rahmutulla, Bahityar, Fukuyo, Masaki, Seki, Motoaki, Hoshii, Takayuki, Sato, Hiroaki, Imamura, Yusuke, Sakamoto, Shinichi, Ichikawa, Tomohiko, Kaneda, Atsushi
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Chromatin - genetics; Chromatin structure; Compartment; Gene Expression Profiling; Histone methyltransferase; Histones - genetics; Histones - metabolism; Humans; Kinesins - metabolism; Male; Metastasis; NSD2; Prostatic Neoplasms, Castration-Resistant - metabolism; Receptors, Androgen - metabolism
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2024.216815

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. •NSD2 is highly expressed in CRPC and its increased expression in PC is associated with poor clinical outcomes.•H3K36me2-elevated regions showed decreased H3K27me3 and inactive to active compartment shift.•Among 68 downstream target genes, KIF18A is critical for PC genesis.