Department of Urologic Sciences, University of British Columbia, Vancouver Prostate Centre, Vancouver, Canada.
British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia, Canada and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
Nucleic Acids Res. 2022 Jan 25;50(2):1069-1091. doi: 10.1093/nar/gkab1247.
We report a new mechanism of androgen receptor (AR) mRNA regulation and cytoprotection in response to AR pathway inhibition (ARPI) stress in prostate cancer (PCA). AR mRNA translation is coordinately regulated by RNA binding proteins, YTHDF3 and G3BP1. Under ambient conditions m6A-modified AR mRNA is bound by YTHDF3 and translationally stimulated, while m6A-unmodified AR mRNA is bound by G3BP1 and translationally repressed. When AR-regulated PCA cell lines are subjected to ARPI stress, m6A-modified AR mRNA is recruited from actively translating polysomes (PSs) to RNA-protein stress granules (SGs), leading to reduced AR mRNA translation. After ARPI stress, m6A-modified AR mRNA liquid-liquid phase separated with YTHDF3, while m6A-unmodified AR mRNA phase separated with G3BP1. Accordingly, these AR mRNA messages form two distinct YTHDF3-enriched or G3BP1-enriched clusters in SGs. ARPI-induced SG formation is cell-protective, which when blocked by YTHDF3 or G3BP1 silencing increases PCA cell death in response to ARPI stress. Interestingly, AR mRNA silencing also delays ARPI stress-induced SG formation, highlighting its supportive role in triggering this stress response. Our results define a new mechanism for stress adaptive cell survival after ARPI stress involving SG-regulated translation of AR mRNA, mediated by m6A RNA modification and their respective regulatory proteins.
我们报告了一种新的雄激素受体 (AR) mRNA 调控机制和前列腺癌 (PCA) 中 AR 通路抑制 (ARPI) 应激的细胞保护作用。AR mRNA 的翻译是由 RNA 结合蛋白 YTHDF3 和 G3BP1 协调调控的。在环境条件下，m6A 修饰的 AR mRNA 与 YTHDF3 结合并被翻译激活，而 m6A 未修饰的 AR mRNA 与 G3BP1 结合并被翻译抑制。当 AR 调节的 PCA 细胞系受到 ARPI 应激时，m6A 修饰的 AR mRNA 从活跃翻译的多核糖体 (PS) 募集到 RNA-蛋白质应激颗粒 (SG)，导致 AR mRNA 翻译减少。在 ARPI 应激后，m6A 修饰的 AR mRNA 与 YTHDF3 液-液相分离，而 m6A 未修饰的 AR mRNA 与 G3BP1 液-液相分离。因此，这些 AR mRNA 消息在 SG 中形成两个不同的 YTHDF3 富集或 G3BP1 富集簇。ARPI 诱导的 SG 形成具有细胞保护作用，当通过 YTHDF3 或 G3BP1 沉默阻断时，会增加 PCA 细胞对 ARPI 应激的死亡。有趣的是，AR mRNA 沉默也会延迟 ARPI 应激诱导的 SG 形成，突出了其在触发这种应激反应中的支持作用。我们的结果定义了一种新的机制，即在 ARPI 应激后，通过 m6A RNA 修饰及其各自的调节蛋白介导的 SG 调节的 AR mRNA 翻译，涉及应激适应性细胞存活。
