RNA-binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: A mechanism of castration resistance

Significance Little is known regarding the mechanisms involved in loss of androgen receptor (AR) function in the development of castration resistance. Recently, the clinical use of new potent AR therapies has led to the emergence of a new lethal subtype of castration-resistant prostate cancer (CRPC) lacking AR protein and signaling, termed ARL/negative CRPC. We discovered that DDX3 (DEAD-box helicase 3 X-linked) is a key repressor of AR protein translation—a mechanism that leads to development of castration resistance. Inhibition of DDX3 in ARL/negative CRPC promotes the expression of AR protein/signaling and hence sensitivity to hormone therapy. These data provide a molecular mechanism for hormone action and describe a synthetic lethality approach to the clinical treatment of therapy-resistant diseases such as CRPC.