REGγ potentiates TGF-β/Smad signal dependent epithelial-mesenchymal transition in thyroid cancer cells.

Thyroid cancer is the most common endocrine cancer with an increasing incidence and mortality. Epithelial-mesenchymal transition (EMT) is a biological process contributing to tumor progression, metastasis, and the acquisition of chemotherapy resistance. The impact of the REGγ proteasome activator on EMT in human thyroid cancer cells and the molecular mechanism is still unclear. Here, we found silencing REGγ in thyroid cancer cells inhibited cell migration and invasion, with concurrent upregulation of E-cadherin and Smurf2 expression. Mechanistically, REGγ dependent regulation of Smurf2, an E3 ligase for Smad3, contributed to alteration of Zeb1/2, Snail, Slug, and Twist. Consistently, TGF-β mediated suppression of E-cadherin was attenuated in REGγ deficient cells, coupled with changes in cell morphology, migration and invasion. Furthermore, xenograft metastasis mouse model showed a reduced E-cadherin expression at both mRNA and protein levels, and decreased cell migration. Taken together, our findings provided an important evidence for the role of REGγ in tumor suppression, thereby implicating REGγ as a potential anti-cancer strategy in thyroid cancer therapy.