Truncated Androgen Receptor Splice Variants: Homodimerize or Heterodimerize.

摘要

Constitutively-active androgen receptor splice variants (AR-Vs) that lack the ligand-binding domain have been implicated to play an important role in mediating castration-resistant progression of prostate cancer. AR-Vs have been shown to regulate the expression of both canonical AR targets and a unique set of targets enriched for cell-cycle function. However, little is known about how regulation of gene expression by AR-Vs is achieved. We are the first to show that AR-Vs not only homodimerize and heterodimerize with each other but also heterodimerize with the full-length AR (AR-FL). Significantly, dimerization is required for the trans-activating activity of AR-Vs. To date, the ability of AR-Vs to regulate gene expression has been attributed largely to their AR-FL-independent activity. Based on our finding and the fact that AR-Vs are often co-expressed with AR-FL in biological context, we believe that the ability of AR-V to heterodimerize with and activate AR-FL in an androgen- independent manner could be as important, if not more important, than its AR-FL- independent activity to castration resistance. The research therefore represents a key step in delineating the mechanism of activation of AR-Vs, which is vital for developing effective means to suppress AR-V signaling for more effective treatment of prostate cancer.