In the present study, we demonstrated that TSA resulted in the activation of ERK1/2 in ESCC cells, whereas inhibition of ERK1/2 activity via application of the MEK1/2 inhibitor U0126 prevented TSA‐induced ESCC migration, EMT, and upregulation of Slug levels, thus suggesting the ERK1/2‐slug pathway as a critical regulator of EMT in TSA‐induced ESCC migration. The gene discussed is MAP2K1; the disease is esophageal squamous cell carcinoma.