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 转录辅阻遏物 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) 患者预后相关的最重要的基因组因素。RB的缺失可以以不依赖于激素的方式支持前列腺癌细胞的生长，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 可使 AKT 信号传导失活，但对癌细胞中的 mTOR 信号传导没有影响。在这里，我们通过 FXXXV 作图发现，RB 中的 S249/T252 位点是调节 CRPC 中肿瘤促进因子 TRIM24 转录活性的关键。 RB/TRIM24 复合物通过 DUSP2 发挥作用，DUSP2 作为中间桥，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，它降低了TRIM24蛋白水平并使mTOR信号通路失活，从而抑制前列腺癌。因此，本研究不仅阐明了RB的新功能，也为开发治疗前列腺癌的新药提供了理论依据。