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Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen

Dinuka De Silva1,2, Zhentao Zhang3,4, Yuanbo Liu3,5

  • 1Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Scientific Reports
|December 11, 2019
PubMed

Insights

Aberrant androgen receptor (AR) activation drives castration-resistant prostate cancer. Ack1 kinase regulates AR interaction with SLIRP, a corepressor influencing androgen-regulated genes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Aberrant androgen receptor (AR) activation is crucial in castration-resistant prostate cancer.
  • AR regulates gene transcription via androgen responsive elements (AREs) through interactions with coactivators and corepressors.

Purpose of the Study:

  • To investigate the downstream mechanisms of AR regulation by Ack1/TNK2 tyrosine kinase.
  • To identify proteins interacting with AR in an Ack1-dependent manner.
  • To elucidate the role of SLIRP in AR-mediated transcription.

Main Methods:

  • Phosphorylation site mapping of AR.
  • Co-immunoprecipitation assays to identify protein interactions.
  • RNA immunoprecipitation (RIP) to assess SLIRP binding to AREs.
  • Whole transcriptome analysis (RNA-seq) following SLIRP knockdown.

Main Results:

  • Ack1 phosphorylates AR at Tyr-267, promoting nuclear translocation and DNA binding in low androgen conditions.
  • SLIRP was identified as an AR-interacting protein whose interaction is modulated by Ack1, androgen, and heregulin.
  • SLIRP binds to AREs in the absence of androgen and dissociates upon androgen or heregulin treatment.
  • SLIRP knockdown significantly affects a subset of androgen-regulated genes, indicating its role as a coregulator.

Conclusions:

  • Ack1 kinase and androgen signaling regulate the interaction between AR and SLIRP.
  • SLIRP functions as a context-dependent corepressor for AR, impacting gene transcription in prostate cancer.

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