TRAF4 protein shows role in resistance to androgen deprivation therapy in prostate cancer

Overexpression of the TRAF4 protein was shown to promote the development of castration-resistant prostate cancer (CRPC) by “[increasing] intracellular cAMP levels and [boosting] E2F transcription factor activity,” according to findings from a recent study.^1,2

For the study, the investigators analyzed cells from patients with metastatic cancer who underwent androgen-deprivation therapy.

"Within certain circumstances where male hormone levels are reduced to castration conditions, we have identified a specific chemical alteration that takes place on the AR [androgen receptor] protein. This modification is linked to the presence of another protein known as TRAF4, which is frequently overexpressed in advanced prostate cancers. Through laboratory experiments and analysis of live samples, we successfully demonstrated that the overexpression of TRAF4 prompts the conversion of androgen-sensitive prostate cancer cells into castration-resistant cells,” said Ping Yi, PhD, in a news release on the findings.² Yi is an assistant professor of biology and biochemistry at Baylor College of Medicine in Houston, Texas.

For the study, the investigators analyzed cells from patients with metastatic cancer who underwent androgen-deprivation therapy (ADT). The cells from patients who were unresponsive to ADT were found to have higher levels of TRAF4 expression compared with the cells of patients who experienced a response to the therapy.

"Additionally, our investigation revealed that the level of TRAF4 protein is elevated in androgen-insensitive lymph node carcinoma cells of the prostate,” Yi added.

According to the authors, TRAF4 may promote CRPC progression by mediating ubiquitination of AR through an atypical K27-link, which leads to an increased interaction between AR and FOXA1, a pioneer factor that changes the genomic binding profile with increased affinity to AR. This initiates an AR-regulated transcriptional reprogramming that causes increased intracellular cAMP levels and hyperactivated E2F, which may allow cancer to metastasize in patients, even with reduced testosterone.

The authors concluded, “Our studies lay the foundation for identifying an appropriate CRPC patient population sensitive to CDK4/6 inhibitor treatment.”

References

1. Singh R, Meng H, Shen T, et al. TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer. Proc Natl Acad Sci U S A. Published online May 8, 2023. Accessed June 15, 2023. doi:10.1073/pnas.2218229120

2. Study identifies potential treatment target for prostate cancer resistant to hormone therapy. News release. University of Houston. June 12, 2023. Accessed June 15, 2023. https://www.newswise.com/articles/target-found-for-prostate-cancer-resistant-to-hormone-therapy?sc=mwhr&xy=10016681