Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin

Oncogene. 2014 May 8;33(19):2441-53. doi: 10.1038/onc.2013.220. Epub 2013 Jun 17.

Abstract

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPβ expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPβ-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.

Publication types

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

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Chromatin Immunoprecipitation
  • Epithelial Cells / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Immunoblotting
  • Integrin alpha5 / biosynthesis*
  • Integrin alpha5 / genetics
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transfection

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Integrin alpha5
  • RNA, Small Interfering
  • SMARCA2 protein, human
  • Transcription Factors