Specific phenotypic effects of PTEN in head and neck squamous cell carcinoma (HNSCC) remain poorly defined without a direct causal connection between the loss of PTEN function and the progression of cancer. Here, we describe a potential role for PTEN in cancer progression. Using an shRNA targeting PTEN in HNSCC cells, we show that the loss of PTEN expression is associated with a decrease of cell adhesion, a reduction in E-cadherin expression while cell migration is promoted. Together with the tissue organization and molecular markers expressed in tumors derived from shPTEN cells in vivo, this study indicates that HNSCC cells deficient in PTEN expression undergo an epithelial‑mesenchymal transition (EMT). Additionally, our results suggest that both the low levels of expression and subcellular localization of PTEN are involved in the EMT phenotype, and ultimately in possible locoregional reccurences. We hypothesize that the loss of PTEN expression as well as the subcellular localization could be of interest as a predictive marker of recurrence in HNSCC.