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Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer

Cell Death & Differentiation (2024)Cite this article

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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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Fig. 1: RB enhances TRIM24 transcriptional activity in PC cells.
Fig. 2: RB interacts with TRIM24 in a phosphorylation-dependent manner.
Fig. 3: The RB N-terminus interacts with TRIM24 to activate mTOR signaling in prostate cancer cells.
Fig. 4: DUSP2 bridges the RB/TRIM24 complex and the mTOR signaling pathway in prostate cancer cells.
Fig. 5: An RB-R-linker derived from RB-S249/T252 inactivated the mTOR signaling pathway in prostate cancer cells.
Fig. 6: A PROTAC derived from the RB-R-linker inhibited the proliferation of prostate cancer cells by mediating mTOR signaling pathway inactivation.
Fig. 7: A model depicting that the S249/T252 site in RB recognizing the “FXXXV” motif of TRIM24 to decrease the expression of DUSP2 and activate the mTOR signaling pathway in PC cells.

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References

  1. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol Cell. 2019;73:22–35.e26

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Zheng Z, Zhang J, Wang Y, Kong R, Liu J, et al. A novel retinoblastoma protein (RB) E3 ubiquitin ligase (NRBE3) promotes RB degradation and is transcriptionally regulated by E2F1 transcription factor. J Biol Chem. 2015;290:28200–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pennaneach V, Barbier V, Regazzoni K, Fotedar R, Fotedar A. Rb inhibits E2F-1-induced cell death in a LXCXE-dependent manner by active repression. J Biol Chem. 2004;279:23376–83.

    Article  CAS  PubMed  Google Scholar 

  6. Groner AC, Cato L, de Tribolet-Hardy J, Bernasocchi T, Janouskova H, Melchers D, et al. TRIM24 Is an oncogenic transcriptional activator in prostate cancer. Cancer Cell. 2016;29:846–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Theurillat JP, Udeshi ND, Errington WJ, Svinkina T, Baca SC, Pop M, et al. Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science. 2014;346:85–89.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shah VV, Duncan AD, Jiang S, Stratton SA, Allton KL, Yam C, et al. Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer. Nat Commun. 2021;12:5389.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wei W, Chen Q, Liu M, Sheng Y, OuYang Q, Feng W, et al. TRIM24 is an insulin-responsive regulator of P-bodies. Nat Commun. 2022;13:3972.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fong KW, Zhao JC, Song B, Zheng B, Yu J. TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression. Nat Commun. 2018;9:5007.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  11. Huang Z, Li X, Tang B, Li H, Zhang J, Sun R, et al. SETDB1 modulates degradation of phosphorylated RB and anticancer efficacy of CDK4/6 inhibitors. Cancer Res. 2023;83:875–89.

    Article  CAS  PubMed  Google Scholar 

  12. Han W, Liu M, Han D, Li M, Toure AA, Wang Z, et al. RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition. Oncogene. 2022;41:852–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou Y, Jin X, Ma J, Ding D, Huang Z, Sheng H, et al. HDAC5 loss impairs RB repression of pro-oncogenic genes and confers CDK4/6 inhibitor resistance in cancer. Cancer Res. 2021;81:1486–99.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang J, Xu K, Liu P, Geng Y, Wang B, Gan W, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell. 2016;62:929–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Davoodi-Moghaddam Z, Jafari-Raddani F, Delshad M, Pourbagheri-Sigaroodi A, Bashash D. Inhibitors of the PI3K/AKT/mTOR pathway in human malignancies; trend of current clinical trials. J Cancer Res Clin Oncol. 2023;149:15293–310.

    Article  CAS  PubMed  Google Scholar 

  16. Shen M, Lv D, Liu X, Wang C. ERK/mTOR signaling may underlying the antidepressant actions of rapastinel in mice. Transl Psychiatry. 2022;12:522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu N, Gou X, Hu P, Chen Y, Ji J, Wang Y, et al. Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs. Virol J. 2022;19:228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ding S, Gao Y, Lv D, Tao Y, Liu S, Chen C, et al. DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway. EBioMedicine. 2022;81:104100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qiu S, Xie L, Lu C, Gu C, Xia Y, Lv J, et al. Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. J Exp Clin Cancer Res. 2022;41:296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pearson RC, Funnell AP, Crossley M. The mammalian zinc finger transcription factor Kruppel-like factor 3 (KLF3/BKLF). IUBMB Life. 2011;63:86–93.

    Article  CAS  PubMed  Google Scholar 

  21. Vizcaino C, Mansilla S, Portugal J. Sp1 transcription factor: a long-standing target in cancer chemotherapy. Pharmacol Ther. 2015;152:111–24.

    Article  CAS  PubMed  Google Scholar 

  22. Caria CA, Faa V, Ristaldi MS. Kruppel-like factor 1: a pivotal gene regulator in erythropoiesis. Cells. 2022;11:3069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Han W, Liu M, Han D, Toure AA, Li M, Besschetnova A, et al. Exploiting the tumor-suppressive activity of the androgen receptor by CDK4/6 inhibition in castration-resistant prostate cancer. Mol Ther. 2022;30:1628–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yedla P, Babalghith AO, Andra VV, Syed R. PROTACs in the management of prostate cancer. Molecules. 2023;28:3698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005;122:947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature. 2014;513:251–5.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaya-Okur HS, Wu SJ, Codomo CA, Pledger ES, Bryson TD, Henikoff JG, et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat Commun. 2019;10:1930.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

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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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Author notes

  1. These authors contributed equally: Da Ren, Wei Li, Ruijiang Zeng, Xinlin Liu.

Authors and Affiliations

  1. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China

    Da Ren, Wei Li, Ruijiang Zeng, Xinlin Liu, Huaiyuan Liang, Wei Xiong & Xin Jin

  2. Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China

    Da Ren, Wei Li, Ruijiang Zeng, Xinlin Liu, Huaiyuan Liang, Wei Xiong & Xin Jin

  3. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Chunguang Yang

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Contributions

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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Correspondence to Chunguang Yang or 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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