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Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor

Yuichiro Kanno1, Shuai Zhao, Naoya Yamashita

  • 1Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University.

The Journal of Toxicological Sciences
|November 13, 2015
PubMed

Insights

Androgen receptor (AR) signaling represses DEPTOR, an mTOR inhibitor, in prostate cancer cells. This AR-driven decrease in DEPTOR promotes cancer cell proliferation by activating mTORC1 signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Crosstalk between androgen receptor (AR) and mammalian target of rapamycin (mTOR) signaling pathways is critical for prostate cancer cell proliferation.
  • DEPTOR, a natural inhibitor of mTOR, is implicated in this process.

Purpose of the Study:

  • To elucidate the mechanism by which AR signaling influences DEPTOR expression and its role in prostate cancer cell proliferation.
  • To investigate the direct transcriptional regulation of DEPTOR by AR.

Main Methods:

  • Utilized LNCaP human prostate cancer cell line.
  • Administered dihydrotestosterone (DHT) as an AR agonist and bicalutamide as an AR antagonist.
  • Employed siRNA for DEPTOR mRNA knockdown.
  • Performed Western blotting to assess S6K phosphorylation and cyclin D1 expression.
  • Conducted Chromatin immunoprecipitation (ChIP) assays to determine AR binding to the DEPTOR gene.
  • Analyzed histone acetylation levels.

Main Results:

  • DHT treatment repressed DEPTOR mRNA expression in a time-dependent manner, an effect blocked by bicalutamide.
  • DEPTOR knockdown led to increased mTORC1 activity (S6K phosphorylation) and elevated cyclin D1 expression, promoting proliferation.
  • ChIP assays confirmed AR binding to a regulatory region within the DEPTOR gene.
  • DHT treatment reduced histone acetylation (Lys9, Lys14) in this AR-binding region, indicating transcriptional repression.

Conclusions:

  • AR directly represses DEPTOR transcription through binding to a specific regulatory element in the DEPTOR gene.
  • Decreased DEPTOR expression induced by AR signaling enhances prostate cancer cell proliferation via mTORC1 activation.

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