title: beta-Catenin activates the growth factor endothelin-1 in colon cancer cells.
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.
authors.affiliation: Laboratory of Gene Regulation, Ludwig Institute for Cancer Research, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
mesh_terms: D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D019332:Endothelin-1; D006133:Growth Substances; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin