Integrative Genomics Analysis Reveals Silencing of Beta-Adrenergic Signaling by Polycomb in Prostate Cancer

Cancer Cell. 2007 Nov;12(5):419-31. doi: 10.1016/j.ccr.2007.10.016.

Abstract

The Polycomb group (PcG) protein EZH2 possesses oncogenic properties for which the underlying mechanism is unclear. We integrated in vitro cell line, in vivo tumor profiling, and genome-wide location data to nominate key targets of EZH2. One of the candidates identified was ADRB2 (Adrenergic Receptor, Beta-2), a critical mediator of beta-adrenergic signaling. EZH2 is recruited to the ADRB2 promoter and represses ADRB2 expression. ADRB2 inhibition confers cell invasion and transforms benign prostate epithelial cells, whereas ADRB2 overexpression counteracts EZH2-mediated oncogenesis. ADRB2 is underexpressed in metastatic prostate cancer, and clinically localized tumors that express lower levels of ADRB2 exhibit a poor prognosis. Taken together, we demonstrate the power of integrating multiple diverse genomic data to decipher targets of disease-related genes.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • DNA-Binding Proteins / metabolism*
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Silencing*
  • Genomics*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Neoplasm Transplantation
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, Adrenergic, beta-2 / physiology*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Receptors, Adrenergic, beta-2
  • Transcription Factors
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2