1. ¹Laboratory of Gene Regulation, Ludwig Institute for Cancer Research, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
2. ²The Burnham Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA
3. ³Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA

Correspondence: B Ren, E-mail: biren@ucsd.edu; Z Zhang, E-mail: benzz@burnham.org

Received 17 April 2004; Revised 21 September 2004; Accepted 23 September 2004; Published online 22 November 2004.

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