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β-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 β-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 β-catenin in colon cancer cells. A specific DNA element within the EDN1 promoter is required for activation, and is associated with β-catenin's cognate DNA binding partner, TCF4, in vivo. Inhibition of β-catenin signaling results in lowered expression of EDN1, while enhancement of β-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 β-catenin. Furthermore, EDN1 is able to rescue colon cancer cells from growth arrest and apoptosis resulting from inhibition of β-catenin signaling, implicating a key role of EDN1 in promoting the oncogenic function of β-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.

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Acknowledgements

We thank Frank Furnari for his assistance with the FACS analysis, Bert Vogelstein and Ken Kinzler for providing the HT29-APC cell line and the GST-TCF4 expression construct, Hans Clevers for providing the TCF4 and β-catenin expression constructs, Linda Wasserman for providing the primary human colon samples, Christine Cheng for her help in constructing the mutant EDN1 reporters, and Webster Cavenee for his comments on the manuscript. THK was supported by Ruth L Kirschstein National Research Service Award #1F32CA108313. This work was supported by the generous funds from PCRP of DOD (BR) Sidney Kimmel Foundation (BR) Charlotte Geyer Foundation (BR) Charlotte Gayer Foundation (BR) and Ludwig Institute for Cancer Research (BR).

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Correspondence to Zhuohua Zhang or Bing Ren.

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Kim, T., Xiong, H., Zhang, Z. et al. β-Catenin activates the growth factor endothelin-1 in colon cancer cells. Oncogene 24, 597–604 (2005). https://doi.org/10.1038/sj.onc.1208237

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  • DOI: https://doi.org/10.1038/sj.onc.1208237

Keywords

  • β-catenin
  • endothelin-1
  • colon cancer
  • ChIP
  • promoter arrays

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