Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China.
Cell Death Differ. 2024 May;31(5):592-604. doi: 10.1038/s41418-024-01282-w. Epub 2024 Mar 21.
RB transcriptional corepressor 1 (RB) deletion is the most important genomic factor associated with the prognosis of castration-resistant prostate cancer (CRPC) patients receiving androgen receptor (AR) signaling inhibitor therapy. Loss of RB could support prostate cancer cell growth in a hormone-independent manner, but the underlying mechanism by which RB regulates tumor progression extends far beyond the cell cycle pathway. A previous study indicated that RB inactivates AKT signaling but has no effect on mTOR signaling in cancer cells. Here, we found that the S249/T252 site in RB is key to regulating the transcriptional activity of the tumor-promoting factor TRIM24 in CRPC, as identified through FXXXV mapping. The RB/TRIM24 complex functions through DUSP2, which serves as an intermediate bridge, to activate the mTOR pathway and promote prostate cancer progression. Accordingly, we designed RB-linker-proteolysis-targeting chimera (PROTAC) molecules, which decreased TRIM24 protein levels and inactivated the mTOR signaling pathway, thereby inhibiting prostate cancer. Therefore, this study not only elucidates the novel function of RB but also provides a theoretical basis for the development of new drugs for treating prostate cancer.
RB 转录核心抑制因子 1（RB）缺失是与接受雄激素受体（AR）信号抑制剂治疗的去势抵抗性前列腺癌（CRPC）患者预后最相关的重要基因组因素。RB 的缺失可以支持前列腺癌细胞在激素非依赖的方式下生长，但 RB 调节肿瘤进展的潜在机制远远超出了细胞周期途径。先前的一项研究表明，RB 可以使 AKT 信号失活，但对癌细胞中的 mTOR 信号没有影响。在这里，我们发现 RB 中的 S249/T252 位点是通过 FXXXV 作图鉴定的，是调节 CRPC 中促肿瘤因子 TRIM24 转录活性的关键。RB/TRIM24 复合物通过作为中间桥接物的 DUSP2 来激活 mTOR 通路并促进前列腺癌进展。因此，我们设计了 RB 连接蛋白水解靶向嵌合体（PROTAC）分子，这些分子降低了 TRIM24 蛋白水平并使 mTOR 信号通路失活，从而抑制了前列腺癌。因此，这项研究不仅阐明了 RB 的新功能，还为开发治疗前列腺癌的新药提供了理论依据。
