DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor

Androgen receptor (AR) activation is critical for prostate cancer development and progression, including castration-resistance. The nuclear export signal of AR (NES(AR)) plays an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NES(AR). DHX15 stabilized Siah2 and enhanced its E3 ubiquitin ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in prostate cancer specimens and its expression was correlated with Gleason scores and PSA recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to prostate cancer progression through Siah2.