Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis

Lu Tong, Shihui Shen, Quan Huang, Junjiang Fu, Tianzhen Wang, Linian Pan, Pei Zhang, Geng Chen, Tingmei Huang, Ke Li, Qingwu Liu, Shaofang Xie, Xiao Yang, Robb E. Moses, Xiaotao Li, Lei Li

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Lung cancer is one of the cancers with highest morbidity and mortality rates and the metastasis of lung cancer is a leading cause of death. Mechanisms of lung cancer metastasis are yet to be fully understood. Herein, we demonstrate that mice deficient for REGγ, a proteasome activator, exhibited a significant reduction in tumor size, numbers, and metastatic rate with prolonged survival in a conditional Kras/p53 mutant lung cancer model. REGγ enhanced the TGFβ-Smad signaling pathway by ubiquitin-ATP-independent degradation of Smad7, an inhibitor of the TGFβ pathway. Activated TGFβ signaling in REGγ-positive lung cancer cells led to diminished expression of E-cadherin, a biomarker of epithelial–mesenchymal transitions (EMT), and elevated mesenchymal markers compared with REGγ-deficient lung cancer cells. REGγ overexpression was found in lung cancer patients with metastasis, correlating with the reduction of E-Cadherin/Smad7 and a poor prognosis. Overall, our study indicates that REGγ promotes lung cancer metastasis by activating TGF-β signaling via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for lung cancers with poor prognosis.

Original languageEnglish (US)
Pages (from-to)1795-1806
Number of pages12
JournalCell Death and Differentiation
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Tong, L., Shen, S., Huang, Q., Fu, J., Wang, T., Pan, L., Zhang, P., Chen, G., Huang, T., Li, K., Liu, Q., Xie, S., Yang, X., Moses, R. E., Li, X., & Li, L. (2020). Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis. Cell Death and Differentiation, 27(6), 1795-1806. https://doi.org/10.1038/s41418-019-0459-6