RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression
Miyeong Kim, … , Xiaoqi Liu, Ka-Wing Fong
Miyeong Kim, … , Xiaoqi Liu, Ka-Wing Fong
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e185119. https://doi.org/10.1172/JCI185119.
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Research Article Cell biology Endocrinology

RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression

Abstract

Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a E2F1 target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcriptional activation and genomic function of E2F1 independent of retinoblastoma (Rb) status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and, as such, RSK1 drives the TRIM28/E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1–TRIM28–E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.

Authors

Miyeong Kim, Jinpeng Liu, Yanquan Zhang, Ruixin Wang, Ryan Goettl, Jennifer Grasso, Derek B. Allison, Chi Wang, Tianyan Gao, Xiaoqi Liu, Ka-Wing Fong

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Figure 7

Exploitation of the RSK1-TRIM28–E2F1 axis as a vulnerability in Rb1-deficient prostate cancer.

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Exploitation of the RSK1-TRIM28–E2F1 axis as a vulnerability in Rb1-defi...
(A and B) C4-2B and DU145 cells treated with RSK inhibitors were analyzed by immunoblot. (C and D) C4-2B with Rb knockdown and DU145 cells treated by vehicle (Veh), 500 nM palbociclib (Pal), 1 μM BI-D1870 (BI), and 20 μM LJH685 (LJH) were subjected to the colony formation assay. Quantification was conducted by image J and presented as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. **P < 0.01, ***P < 0.001. (E and F) PCa organoids were generated from prostate tumors in Pb-Cre:Pten–/– mice. (E) Representative images were shown. (F) Quantification was presented as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. ***P < 0.001. (G) The experimental design of LuCaP145.1 PDX assay and treatment strategy. (H–J) NGS mice were implanted subcutaneously with LuCaP 145.1 tumors. Mice were randomized and treated with vehicle, palbociclib (75 mg/kg) and BI-D1870 (50 mg/kg) for 3 weeks. Tumor sizes were plotted against days of treatment (H). The tumor volume data were presented as mean ± SEM, n = 5. The statistical analysis was performed using a 1-way ANOVA with Tukey’s HSD test for multiple comparisons P value adjustment. ***P < 0.001. Tumor weight was presented as boxplot (I), and the toxicity was evaluated by mouse body weight (J). The data was presented as mean ± SEM, n = 5. Two-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. *P < 0.05. (K–N) Tumor tissues were subjected to IHC assay. Magnification ×20. (K), followed by quantification (L–N). The data was presented as mean ± SEM, n = 5. Two-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. ***P < 0.001.