RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression
Miyeong Kim, Jinpeng Liu, Yanquan Zhang, Ruixin Wang, Ryan Goettl, Jennifer Grasso, Derek B. Allison, Chi Wang, Tianyan Gao, Xiaoqi Liu, Ka-Wing Fong
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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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 3

TRIM28 controls E2F1 genomic binding and E2F target expression in CRPC.

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TRIM28 controls E2F1 genomic binding and E2F target expression in CRPC. ...
(A–D) TRIM28 regulates E2F1 cistrome in CRPC. E2F1 CUT&RUN-seq was performed using LNCaP cells with LKO and shTRIM28. E2F1 peak was called by MACS2. Venn diagram indicates the overlapping of E2F1 binding sites for each treatment (A). Intensity plot depicts the CUT&RUN-seq peak intensity around peak center ±5 kb (B). Heatmaps indicate E2F1 CUT&RUN-seq signal at E2F1 binding sites ±2 kb (C). Genome browser tracks indicate E2F1 enrichment at the MCM3 genome in the replicates of LKO and shTRIM28. IgG CUT&RUN-seq as negative control (D). (E and F) E2F1-ChIP was performed in LNCaP cells with indicated treatment (E), and E2F1 enrichment at representative E2F targets was evaluated by qPCR (F). 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 < 0.05, **P < 0.01, ns: not significant. (G) Heatmap showing the levels of E2F-target genes in the CRPC samples from SUC12 2015 study (n = 118) sorted by TRIM28.