TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Highlights

• TRIM24 mediates tumor cell proliferation in SPOP mutant PC and CRPC

• TRIM24 activates pro-proliferative genes together with AR in CRPC

• TRIM24 protein increases in CRPC and predicts disease recurrence

• The TRIM24 bromodomain mediates CRPC growth and is a potential drug target

Summary

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.