beta-Catenin activates the growth factor endothelin-1 in colon cancer cells

Oncogene. 2005 Jan 20;24(4):597-604. doi: 10.1038/sj.onc.1208237.

Abstract

Endothelin-1 (EDN1) is a growth factor that is frequently produced by cancer cells and plays a critical role in tumorigenesis. However, the molecular mechanism controlling the expression of EDN1 in cancers is unknown. Constitutive activation of beta-catenin pathway is responsible for the initiation of the vast majority of colon cancers. Here we show that the EDN1 gene is directly regulated by beta-catenin in colon cancer cells. A specific DNA element within the EDN1 promoter is required for activation, and is associated with beta-catenin's cognate DNA binding partner, TCF4, in vivo. Inhibition of beta-catenin signaling results in lowered expression of EDN1, while enhancement of beta-catenin signaling leads to further activation of the gene. Significantly elevated EDN1 expression occurs in 80% of primary human colon cancers, consistent with it being a direct target of beta-catenin. Furthermore, EDN1 is able to rescue colon cancer cells from growth arrest and apoptosis resulting from inhibition of beta-catenin signaling, implicating a key role of EDN1 in promoting the oncogenic function of beta-catenin. These results indicate EDN1 overexpression as a major cause in colon cancers and reveal further details of the genetic programs responsible for tumorigenesis of colon cancers.

Publication types

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

MeSH terms

  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Endothelin-1* / genetics
  • Endothelin-1* / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Growth Substances / genetics
  • Growth Substances / metabolism*
  • Humans
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Response Elements / genetics
  • Signal Transduction
  • TCF Transcription Factors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Endothelin-1
  • Growth Substances
  • RNA, Messenger
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • beta Catenin