Epithelial specific ETS-1 (ESE-1) is one of the E26 transformation-specific transcription factor superfamily and could be considerable interest as a possible target for regulating diverse types of human cancer. Despite its clinical importance, the reported biological role of ESE-1 on cancer development and progression are still controversial and its underlying mechanisms of tumorigenesis remains unclear. The objectives of this dissertation are to elucidate the role of ESE-1 in tumorigenesis. With the evidence in cancer phenotypes, the underlying mechanisms of ESE-1 in colon cancer was also investigated. ESE-1 knockout mice increased azoxymethane (AOM) -induced and dextran sulfate sodium (DSS)-promoted formation of aberrant crypt foci (ACF) compared to wild type mice. Overexpression of ESE-1 suppressed anchorage-independent growth and migration/invasion in human colon cancer cells and while knockdown of ESE-1 reversed anti-cancer activity. Full length ESE-1 was abundantly found in the nucleus, and internal deletion of nuclear localization sequence 2 (NLS2) decreased the amount of nuclear ESE-1. Three lysine residues (318KKK320) in the NLS2 were critical for nuclear localization of ESE-1 and mediates tumor suppressive activity of ESE-1 through reduced beta-catenin transcriptional activity. We identified two anti-cancer natural compounds, epigallocatechin-3-gallate (EGCG) and patchouli alcohol as ESE-1 inducers. Both EGCG and patchouli alcohol increased expression of ESE-1 protein and mRNA in human colon cancer cells. Patchouli alcohol showed reduced the number of tumors and tumor load in Apcmin/+ colon cancer animal model although protein expression level of ESE-1 did not show significant difference. These findings suggest a potential use of ESE-1 as a novel and potential molecular target of natural anti-cancer phytochemicals for colon cancer prevention.