is a lncRNA overexpressed in several epithelial cancers and strongly correlated with invasion. This lncRNA was proven a pivotal element of the epithelial-to-mesenchymal transition (EMT), a transdifferentiation process triggering metastasis. Snail, master inducer of EMT, requires to recruit EZH2 on specific epithelial target genes (i.e., , and ) and cause their repression. Here, we designed a deletion mutant form, named - , including the putative Snail-binding domain but depleted of the EZH2-binding domain. - acted as a dominant negative of the endogenous . In both murine and human tumor cells, - impaired the ability of to bind Snail and, in turn, trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes. Notably, - expression was proven to reduce cellular motility, invasiveness, anchorage-independent growth, and responsiveness to TGFβ-induced EMT. These data provide evidence on a lncRNA-based strategy to effectively impair the function of a master EMT-transcriptional factor. SIGNIFICANCE: This study defines an innovative RNA-based strategy to interfere with a pivotal function of the tumor-related lncRNA , comprising a dominant negative mutant that was computationally designed and that impairs epithelial-to-mesenchymal transition.