beta-Catenin activates the growth factor endothelin-1 in colon cancer cells.
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.
Kim
Tae Hoon
TH
Laboratory of Gene Regulation, Ludwig Institute for Cancer Research, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Xiong
Hui
H
Zhang
Zhuohua
Z
Ren
Bing
B
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
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