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 2

TRIM28 regulates the E2F pathway in CRPC.

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TRIM28 regulates the E2F pathway in CRPC. (A–I) TRIM28 induces the E2F p...
(A–I) TRIM28 induces the E2F pathway. RNA-Seq was performed using RNA extracted from C4-2B with LKO and shTRIM28, respectively. GSEA enrichment plots reveal various Cancer Hallmark signatures are induced by TRIM28 (A). C4-2B (B and F), 22Rv1 (C and G), PC3 (D and H), and DU145 (E and I) cells were infected by shRNA targeting TRIM28. RNA was harvested for qPCR analysis of E2F levels (B–E) while protein lysates were subjected to immunoblot analysis against TRIM28 and E2F1 (F–I). qPCR data are shown as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001. (J) E2F1 and TRIM28 gene expression in prostate cell line at different stages was queried from Depmap portal and presented in a scatter plot. Statistical analysis is based on linear regression. (K and L) shRNA-resistant TRIM28 plasmids were introduced into C4-2B cells with shTRIM28. RNA was harvested for qPCR analysis of E2F levels (K) while protein lysates were subjected to immunoblot analysis against TRIM28 and E2F1 (L). qPCR data are shown as mean ± SEM, n = 3. Statistical analysis was performed using a two-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. **P < 0.01, ***P < 0.001. (M and N) Overexpression of TRIM28 upregulates E2F1 expression. C4-2B cells stably expressing HA-Flag tagged TRIM28 were collected for qPCR (M) or immunoblot (N). qPCR data are shown as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001.