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

Chan Jiao, Lin Li, Pei Zhang, Li Zhang, Ke Li, Riqun Fang, Lei Yuan, Kaixuan Shi, Linan Pan, Qiannan Guo, Xiao Gao, Geng Chen, Shichen Xu, Qingwei Wang, Di Zuo, Wei Wu, Shanlou Qiao, Xiaoshuang Wang, Robb Moses, Jianru XiaoLei Li, Yongyan Dang, Xiaotao Li

Research output: Contribution to journalArticle

4 Scopus citations

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 important mediator for the REGγ function in ATC cell dedifferentiation, which is supported by expression profiles in human ATC tissues. It seems that REGγ impinges on repression of thyroid-specific genes and promotion of tumor malignancy in ATC cells by activating the TGF-β signal pathway via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for allowing radioiodine therapy in anaplastic thyroid cancer patients with poor prognosis.

Original languageEnglish (US)
Pages (from-to)497-508
Number of pages12
JournalCell Death and Differentiation
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Jiao, C., Li, L., Zhang, P., Zhang, L., Li, K., Fang, R., Yuan, L., Shi, K., Pan, L., Guo, Q., Gao, X., Chen, G., Xu, S., Wang, Q., Zuo, D., Wu, W., Qiao, S., Wang, X., Moses, R., ... Li, X. (2020). REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway. Cell Death and Differentiation, 27(2), 497-508. https://doi.org/10.1038/s41418-019-0367-9