Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Cancer Res Commun. 2022 Aug 25;2(8):870-883. doi: 10.1158/2767-9764.CRC-22-0126. eCollection 2022 Aug.
Homeostasis of genomic integrity should be regulated to promote proliferation and inhibit DNA damage-induced cell death in cancer. Ribonuclease H2 (RNase H2) maintains genome stability by controlling DNA:RNA hybrid and R-loop levels. Here, we identified that RNase H2 subunit A (RNASEH2A), a component of RNase H2, is highly expressed in castration-resistant prostate cancer (CRPC) tissues compared with localized prostate cancer. Interestingly, we showed that RNASEH2A suppressed R-loop levels to prevent cell apoptosis induced by DNA damage in prostate cancer cells. Both and studies revealed that RNASEH2A promotes cell growth and migration via the negative regulation of p53 and positive regulation of AR and AR-V7. Mechanistically, epigenetic regulation followed by R-loop accumulation in these promoters was observed for these gene regulations. Importantly, IHC analysis demonstrated that R-loop formation increased in CRPC tissues and correlated with RNASEH2A expression levels. Notably, two small molecules targeting RNase H2 activity were found to suppress CRPC tumor growth with no significant toxic effects. Collectively, we propose that RNASEH2A overexpression is a hallmark of prostate cancer progression by maintaining genomic stability to prevent R-loop-mediated apoptosis induction. Targeting RNase H2 activity could be a potential strategy for treating CRPC tumors.
RNASEH2A was demonstrated to be highly upregulated in aggressive prostate cancer to degrade R-loop accumulation and preserve genomic stability for tumor growth, suggesting that RNase H2 activity could be a promising therapeutic target.
基因组完整性的动态平衡应该受到调节，以促进增殖并抑制癌症中 DNA 损伤诱导的细胞死亡。核糖核酸酶 H2（RNase H2）通过控制 DNA：RNA 杂交和 R 环水平来维持基因组稳定性。在这里，我们发现 RNase H2 亚基 A（RNASEH2A）是 RNase H2 的一个组成部分，在去势抵抗性前列腺癌（CRPC）组织中比局部前列腺癌组织中的表达水平更高。有趣的是，我们表明 RNASEH2A 通过抑制 R 环水平来抑制 DNA 损伤诱导的前列腺癌细胞凋亡。和 研究均表明，RNASEH2A 通过负调控 p53 和正调控 AR 和 AR-V7 来促进细胞生长和迁移。从机制上讲，观察到这些基因调控中存在表观遗传调节以及这些启动子中 R 环的积累。重要的是，免疫组化分析表明，R 环形成在 CRPC 组织中增加，并与 RNASEH2A 表达水平相关。值得注意的是，两种靶向 RNase H2 活性的小分子被发现可抑制 CRPC 肿瘤生长，而没有明显的毒性作用。总之，我们提出 RNASEH2A 的过表达是前列腺癌进展的标志，通过维持基因组稳定性来防止 R 环介导的凋亡诱导。靶向 RNase H2 活性可能是治疗 CRPC 肿瘤的一种潜在策略。
RNASEH2A 在侵袭性前列腺癌中表现出高度上调，以降解 R 环积累并维持肿瘤生长的基因组稳定性，这表明 RNase H2 活性可能是一种有前途的治疗靶标。
