REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway.

ABSTRACT: Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REGγ, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REGγ significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the efficacy of ¹³¹I therapy in ATC xenograft models. Mechanistically, REGγ directly binds to the TGF-β signaling antagonist Smad7 and promotes its degradation, leading to the activation of the TGF-β signal pathway. With gain- and loss-of-function studies, we demonstrate that Smad7 is an impor

SUBMITTER: Jiao C 

PROVIDER: S-EPMC7205985 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature