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

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 novel E2F1-target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcription activation and genomic function of E2F1 independent of 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. Examination of the genomic landscape of E2F1 and TRIM28 in human prostate cancer cells LNCaP and C4-2B cells. There are 11 CUT&RUN-seq and 4 ATAC-seq samples.