Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits neoplastic transformation and tumor invasion. Tissue microarray analysis showed that Pdcd4 expression is downregulated in colon adenocarcinoma and carcinoma relative to adjacent normal tissues. To address the issue of whether reduced Pdcd4 expression is sufficient to promote tumor progression, we knocked down Pdcd4 expression in colon tumor HT29 cells using pdcd4 short hairpin RNA (shRNA). Pdcd4 knockdown results in a fibroblast-like transition, while the control cells (expressing LacZ shRNA) remain as clumped similar to the parental cells. In addition, expression of pdcd4 shRNA in HT29 cells promotes invasion. In an effort to characterize the molecular mechanism underlying these observations, we discovered that knockdown of Pdcd4 results in reduction of E-cadherin expression, and accumulation of active beta-catenin in the nucleus. The active beta-catenin binds with T-cell factor 4 (Tcf4) and activates beta-catenin/Tcf-dependent transcription. Furthermore, Pdcd4 knockdown dramatically increases AP-1-dependent transcription. Thus, the mechanism by which reduced Pdcd4 expression promotes invasion appears to involve the activation of beta-catenin/Tcf and AP-1-dependent transcription.