Inhibition of p62 and/or NFE2L2 induced autophagy impaires esophageal squamous cell cancer metastasis by reversing EMT

Esophageal squamous cell carcinoma (ESCC) pathogenesis is influenced by both NFE2L2 (nuclear factor erythroid 2-related factor 2) and SQSTM1 (sequestosome 1), also known as p62. However, while there is evidence that these two proteins can interact with one another in a range of pathological contexts, whether these interactions govern the development or progression of ESCC remains unknown. In the present study, analyses of the GEPIA database revealed the simultaneous upregulation of both NFE2L2 and p62 in ESCC, as was further confirmed through biochemical analyses conducted with a human tumor microarray. Knocking down the expression of one or both of these factors demonstrated that both p62 and NFE2L2 mediate the progression of ESCC, as such downregulation altered the morphological characteristics of these cells and suppressed the epithelial-mesenchymal transition (EMT). Strikingly, these experiments revealed synergistic interactions between NFE2L2 and p62 in the promotion of ESCC invasivity and EMT induction. The treatment of cells with the autophagy inhibitors 3-MA, however, was sufficient to partially reverse the anti-metastatic effects of knocking down p62 and/or NFE2L2. Together, these data illustrate the ability of p62 and NFE2L2 to function in a synergistic manner, promoting ESCC cell metastatic progression and EMT induction through mechanisms linked to autophagic activity. As such, efforts to simultaneously target both of these proteins may represent a viable means of providing new treatment options to ESCC patients.