TY - JOUR
T1 - Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis
AU - Tong, Lu
AU - Shen, Shihui
AU - Huang, Quan
AU - Fu, Junjiang
AU - Wang, Tianzhen
AU - Pan, Linian
AU - Zhang, Pei
AU - Chen, Geng
AU - Huang, Tingmei
AU - Li, Ke
AU - Liu, Qingwu
AU - Xie, Shaofang
AU - Yang, Xiao
AU - Moses, Robb E.
AU - Li, Xiaotao
AU - Li, Lei
N1 - Funding Information:
Acknowledgements This work was supported by the National Basic Research Program of China (2016YFC0902102, 2015CB910402). This study was also funded by the National Basic Research Program (2011CB504200, 2015CB910403). This work was also supported in part by grants from National Natural Science Foundation of China (81401837, 81471066, 81672887, 81261120555, 31200878, 31071875, 81271742, 31401012, 31730017), the Science and Technology Commission of Shanghai Municipality (19140900400, 14430712100), Shanghai Rising-Star Program (16QA1401500), Shanghai natural science foundation (17ZR1407900, 12ZR1409300, 14ZR1411400) and project funded by China Postdoctoral Science Foundation(2019M651434). The authors especially thank Prof Longying Tang for her helpful comments on this manuscript.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075443256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075443256&partnerID=8YFLogxK
U2 - 10.1038/s41418-019-0459-6
DO - 10.1038/s41418-019-0459-6
M3 - Article
AN - SCOPUS:85075443256
VL - 27
SP - 1795
EP - 1806
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 6
ER -