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

Oncogene. 2018 Feb 1;37(5):638-650. doi: 10.1038/onc.2017.371. Epub 2017 Oct 9.


Androgen receptor (AR) activation is critical for prostate cancer (PCa) development and progression, including castration resistance. The nuclear export signal of AR (NESAR) has 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 NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin-ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in PCa specimens and its expression was correlated with Gleason scores and prostate-specific antigen 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 PCa progression through Siah2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Nuclear Export Signals / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prostate / pathology
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • Receptors, Androgen / metabolism*
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / genetics
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • AR protein, human
  • Nuclear Export Signals
  • Nuclear Proteins
  • Receptors, Androgen
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • DHX15 protein, human
  • Prostate-Specific Antigen
  • RNA Helicases