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

  • Cell Death Differ. 2020 Jun;27(6):1795-1806. doi: 10.1038/s41418-019-0459-6.
Lu Tong   #  1 ,  Shihui Shen   #  1 ,  Quan Huang   #  2 ,  Junjiang Fu   #  3 ,  Tianzhen Wang  1 ,  Linian Pan  1 ,  Pei Zhang  4 ,  Geng Chen  1 ,  Tingmei Huang  1 ,  Ke Li  1 ,  Qingwu Liu  1 ,  Shaofang Xie  1 ,  Xiao Yang  5 ,  Robb E Moses  6 ,  Xiaotao Li  7 ,  Lei Li  8
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China.
  • 2. Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, 200003, Shanghai, China.
  • 3. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, 646000, Sichuan, China.
  • 4. Department of Pathology, the Second Chengdu Municipal Hospital, 610017, Chengdu, China.
  • 5. State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 100071, Beijing, China.
  • 6. Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 7. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 31767934 DOI: 10.1038/s41418-019-0459-6
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.

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