The Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the lysine methyltransferase G9a suppresses canonical Wnt signalling by directly activating expression of DKK1, a Wnt antagonist. Inhibition of G9a expression or its pharmacological activity resulted in reduced DKK1 expression and consequently elevated b-catenin levels that impaired growth and induced differentiation of ERMS cells in vitro and in vivo. Loss of DKK1 mimicked G9a depletion phenotypes. Conversely, the impact of G9a deficiency on tumor growth was reversed by recombinant DKK1, or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability. Together, our demonstrate that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1-b-catenin node holds promise for differentiation therapy.