Identification of epithelial-specific ETS-1 (ESE-1) as a tumor suppressor and molecular target of green tea compound, EGCG

Abstract

Epithelial specific ETS-1 (ESE-1) belongs to the E26 transformation-specific transcription factor superfamily and is of great interest as a potential target for managing several types of cancer. Despite its clinical significance, the documented effects of ESE-1 on cancer development and progression are contradictory and its underlying biological mechanism of action remains elusive. The objectives of this study are to investigate whether ESE-1 is a tumor suppressor and to identify dietary anti-cancer compound to activate ESE-1 expression in human colon cancer model. ESE-1 knockout and xenograft mouse models were used to examine the effect of ESE-1 in colon tumorigenesis. Stable human colon cancer cell lines were used for in vitro mechanistic studies. ESE-1 knockout in mice increased azoxymethane (AOM)-induced and dextran sulfate sodium (DSS)-promoted formation of aberrant crypt foci (ACF). Conversely, overexpression of ESE-1 suppressed tumorigenicity in a xenograft mouse study, and repressed anchorage-independent growth and migration/invasion in human colon cancer cells. Full length ESE-1 localized abundantly in the nucleus, and internal deletion of nuclear localization sequence 2 (NLS2) reduced nuclear ESE-1. Three lysine residues ((318) KKK(320) ) in the NLS2 determine its nuclear localization. We identified epigallocatechin-3-gallate (EGCG) that acts as a transcriptional activator of ESE-1 in human colon cancer cells. These findings propose a novel and promising molecular target of dietary anti-cancer compounds for prevention of colon cancer.