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HPP1is a recently discovered gene that is epigenetically silenced in a number of tumor types, suggesting a potential role as a tumor suppressor. However, whetherHPP1has tumor suppressor activity is not clearly known. We have sought to investigate the effects ofHPP1on tumor growth and survival and to identify signaling pathways that mediateHPP1's mechanism of action. Forced expression ofHPP1into HCT116 colon cancer cell lines blocked the ability of HCT116 tumors to grownin vivoin nude mice. In cell culture, ectopic expression ofHPP1induces apoptosis and potently inhibits soft agar colony formation.HPP1overexpression was also associated with a moderate reduction inin vitroproliferation characterized by an accumulation of cells in the G0/G1 phase of the cell cycle. Microarray analysis revealed that ectopic expression ofHPP1resulted in a dramatic upregulation ofSTAT1as well as a large number of associated interferon-inducible genes. RNA interference-mediated abrogation ofSTAT1reversedHPP1's antiproliferative effects. We conclude thatHPP1demonstrates tumor suppressive and pro-apoptotic activity, bothin vitroandin vivo. Coupled with its inactivation in a number of tumor types, our data provides evidence to support the role ofHPP1as a tumor suppressor gene. Moreover, activation of theSTAT1pathway likely represents the principal mediator ofHPP1's tumor suppressive properties.