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Wwox suppresses prostate cancer cell growth through modulation of ErbB2-mediated androgen receptor signaling

Haiyan R Qin1, Dimitrios Iliopoulos, Tatsuya Nakamura

  • 1Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

Molecular Cancer Research : MCR
|August 21, 2007
PubMed

Insights

The WWOX tumor suppressor gene, often lost in prostate cancer, inhibits cancer growth by blocking ERBB2 activation. WWOX

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The WWOX tumor suppressor gene's expression is frequently lost or reduced in various cancers, notably prostate cancer.
  • Previous research demonstrated that WWOX overexpression induces apoptosis and suppresses prostate cancer progression both in vitro and in vivo.

Purpose of the Study:

  • To investigate the specific molecular pathways through which WWOX exerts its tumor-suppressive effects on prostate cancer cell growth.
  • To elucidate the interaction between WWOX, Ap2gamma, and ERBB2 in the context of prostate cancer.

Main Methods:

  • Investigated the interaction between WWOX and Ap2gamma.
  • Assessed the effect of WWOX on the nuclear localization of Ap2gamma and its binding to the ERBB2 promoter.
  • Measured ERBB2 and prostate-specific antigen (PSA) expression levels.
  • Correlated WWOX and ErbB2 protein expression in prostate cancer tissues.

Main Results:

  • WWOX interacts with Ap2gamma, preventing its nuclear entry and subsequent activation of the ERBB2 promoter.
  • Ectopic WWOX expression reduced ErbB2 protein levels in vitro, and WWOX protein levels inversely correlated with ErbB2 protein levels in prostate cancer tissues.
  • WWOX suppressed Ap2gamma/ErbB2-mediated prostate cancer cell growth and PSA secretion, an effect dependent on functional androgen receptor signaling.

Conclusions:

  • WWOX acts as a critical regulator of prostate cancer cell proliferation by inhibiting the Ap2gamma/ERBB2 pathway, particularly under limiting androgen conditions.
  • The tumor-suppressive function of WWOX in prostate cancer is mediated through the down-modulation of ErbB2 and requires an intact androgen receptor pathway.

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