Abstract
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.
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Funding
Chinese National Natural Science Foundation (Grant No. 82073321 (XJ) and 82272910 (XJ). Excellent Youth Foundation of Hunan Scientific Committee (Grant No. 2022JJ10092, (XJ)). Hunan leading program for science and technology innovation of high technology industries (Grant No. 2022GK4020, (XJ)). Central South University Innovation-Driven Research Programme (Grant No.2023CXQD058, XJ). Key scientific research project of Hunan Provincial Health Commission (Grant No.W20242004, XJ).
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Methodology: Da Ren, Wei Li, Ruijiang Zeng, Xinlin Liu. Formal analysis: Huaiyuan Liang, Wei Xiong. Conceptualization: Wei Xiong. Investigation: Chunguang Yang, Xin Jin. Project administration: Xin Jin.
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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya hospital, Central South University.
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Ren, D., Li, W., Zeng, R. et al. Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01282-w
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DOI: https://doi.org/10.1038/s41418-024-01282-w