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
View: Text | PDF
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

×

Figure 1

TRIM28 is an E2F1 target in advanced prostate cancer.

Options: View larger image (or click on image) Download as PowerPoint
TRIM28 is an E2F1 target in advanced prostate cancer. (A–C) Tissue micro...
(A–C) Tissue microarray was subjected to IHC staining with anti-TRIM28 antibody. Representative images of patient samples at different disease stages are shown: (A) BPH, (B) Gleason 7, and (C) Gleason 9. Original magnification ×4; insets ×20. (D) Quantification of TRIM28 IHC intensity scores in BPH, Gleason score < 6, 3 + 4, 4 + 3, and > 8. The y-axis shows the percentage of tumors with weak (blue), moderate (red), and intense (green) IHC scores for each category. (E) Kaplan–Meier plot depicts disease-free survival of PCa patients stratified by TRIM28-high (above median value; red) and -low expression (below median value; blue) (n = 280). Significant differences between groups was determined by 1-way ANOVA. (F and G) Genome browser tracks indicate E2F1 CUT&RUN-seq peak at the promoter region of TRIM28 loci (F). IgG and E2F1 ChIP-PCR were performed in LNCaP cells. qPCR data are shown as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, **P < 0.01. (H–K) C4-2B and DU145 cells were infected by 2 shRNAs targeting E2F1. RNA was harvested for qPCR analysis of TRIM28 mRNA levels (H and I) while protein lysates were subjected to immunoblot analysis (J and K). qPCR data are shown as mean ± SEM, n = 3. Statistical analysis was performed using a 2-tailed unpaired Student’s t test, with the Holm-Bonferroni method applied to correct for multiple comparisons. **P < 0.01, ***P < 0.001. (L and M) C4-2B cells were transiently transfected with empty vector (EV) and HA-E2F1 followed by qPCR (L) and IB (M) analysis against HA and TRIM28. qPCR data are shown as mean ± SEM, n = 3. Two-tailed unpaired Student’s t test, *P < 0.05. (N–P) E2F1 RNA (y-axis) was plotted against TRIM28 RNA (x-axis) using the SUC12 (n = 266) (N), TCGA (n = 492) (O), and Nat Med 2016 (n = 136) (P) datasets. x- and y-axes show normalized expression. Statistical analysis is based on linear regression.