TRIM24 promotes cell proliferation in SPOP-mutant and castration-resistant prostate cancer (CRPC).

  • Major finding: TRIM24 promotes cell proliferation in SPOP-mutant and castration-resistant prostate cancer (CRPC).

  • Mechanism: TRIM24 enhances tumor growth in low-androgen conditions by recruiting AR to target genes.

  • Impact: TRIM24 bromodomain or AR-interacting domain targeting may be beneficial in SPOP-mutant cancer and CRPC.

Recurrent mutations in the ubiquitin ligase adaptor speckle-type POZ protein (SPOP) have been observed in approximately 10% of prostate cancers. SPOP mutations result in reduced ubiquitylation of downstream effector proteins such as tripartite motif-containing protein 24 (TRIM24), a transcriptional regulator that binds to unmodified and acetylated histones through its bromodomain and to several nuclear receptors, including androgen receptor (AR), through its conserved LxxLL motif. However, the role of TRIM24 in prostate cancer is not well characterized. Groner and colleagues demonstrated that SPOP mutants enhanced TRIM24 protein expression in androgen-dependent prostate cancer cells by impairing its ubiquitination and degradation. In low-androgen conditions, SPOP-mutant–mediated expression of TRIM24 promoted prostate cancer cell proliferation. In addition, TRIM24 was found to be upregulated more generally in CRPC, where its expression is essential for CRPC cell growth. At the molecular level, TRIM24 bound to AR target gene promoters and coactivated AR-regulated genes more strongly in limiting hormone conditions. In patients with prostate cancer, higher expression of a 21-gene AR/TRIM24-regulated signature was associated with metastasis and an increased risk of recurrence. TRIM24 expression itself was also associated with tumor aggressiveness; in prostate cancer tissue microarrays, TRIM24 expression increased from benign prostatic hyperplasia to primary tumors and was most highly expressed in CRPC. In mice, TRIM24 overexpressing tumors exhibited increased proliferation, and, following surgical castration, TRIM24-overexpressing tumors were more likely to continue growing than controls, further suggesting that TRIM24 overexpression increases the likelihood of developing CRPC. The effects of TRIM24 on CRPC cell proliferation required both the AR-interacting LxxLL motif and the chromatin-binding bromodomain, suggesting that these interactions may represent potential therapeutic targets in SPOP-mutant cancer and CRPC. Taken together, these findings reveal an oncogenic role for TRIM24 in promoting transcription of AR target genes and provide a rationale for future efforts to target TRIM24 in SPOP-mutant prostate cancer and CRPC.

Groner AC, Cato L, de Tribolet-Hardy J, Bernasocchi T, Janouskova H, Melchers D, et al. TRIM24 is an oncogenic transcriptional activator in prostate cancer. Cancer Cell 2016 May 26 [Epub ahead of print].