Kim Miyeong, Liu Jinpeng, Zhang Yanquan, Wang Ruixin, Goettl Ryan, Grasso Jennifer, Allison Derek B, Wang Chi, Gao Tianyan, Liu Xiaoqi, Fong Ka-Wing
Department of Toxicology and Cancer Biology.
Department of Biostatistics, College of Public Health.
J Clin Invest. 2025 Jun 16;135(12). doi: 10.1172/JCI185119.
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.
去势抵抗性前列腺癌（CRPC）标志着前列腺癌（PCa）的晚期和致死阶段。TRIM28，也称为KAP1，是一种转录调节因子，最近被证明可促进CRPC细胞增殖和异种移植肿瘤生长。然而，关于CRPC中TRIM28上调的潜在机制以及TRIM28调节的基因组靶点，仍存在知识空白。在此，我们报告TRIM28是CRPC中的E2F1靶点。使用综合基因组方法，我们证明TRIM28形成正反馈环，以促进E2F1的转录激活和基因组功能，而与视网膜母细胞瘤（Rb）状态无关。此外，我们鉴定出RSK1是一种在S473处直接磷酸化TRIM28的激酶，因此，RSK1驱动TRIM28/E2F1反馈环。相应地，pS473-TRIM28促进CRPC进展，而RSK抑制可减轻这种进展。总之，我们的研究揭示了RSK1-TRIM28-E2F1轴在CRPC进展中的关键作用，这可能被用作治疗Rb缺陷型CRPC的一个弱点。
