microRNAs(miRNAs) can regulate epithelial-mesenchymal transition (EMT) through transcription factors, however, little is known whether EMT transcription factors can modulate miRNAs and further induce EMT and cancer metastasis. Here we show that overexpression of Snail and Slug leads to a mesenchymal phenotype and morphology and enhances cell invasion along with stem cell properties in squamous cell carcinoma of oral tongue (OTSCC) cells. Repression of miR-101 expression by Snail and Slug is essential for Snail/Slug-induced malignant phenotypes. The suppression of miR-101 subsequently activates EZH2, the sole histone methyltransferase, inducing EMT, migration and invasion of OTSCC cells. Importantly, co-overexpression of Slug and Snail correlates with poor survival and elevated EZH2 expression in two independent patient cohorts of OTSCC specimens. These findings defined a Snail and Slug/miR-101/EZH2 pathway as a novel regulatory axis of EMT-mediated-microRNA signaling.