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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References
Wang L, Yue W, Zhang L, Zhao X, Wang Y, Xu S. mTOR and PTEN expression in non-small cell lung cancer: analysis by real-time fluorescence quantitative polymerase chain reaction and immunohistochemistry. Surg Today. 2012;42:419–25.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl J Med. 2010;362:2380–8.
Lee T, Lee B, Choi YL, Han J, Ahn MJ, Um SW. Non-small cell lung cancer with concomitant EGFR, KRAS, and ALK Mutation: clinicopathologic features of 12 cases. J Pathol Transl Med. 2016;50:197–203.
Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol. 2013;31:1112–21.
Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, et al. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989;246:491–4.
Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–87.
Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001;29:418–25.
Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448:807–10.
Meuwissen R, Berns A. Mouse models for human lung cancer. Genes Dev. 2005;19:643–64.
Otsuki Y, Saya H, Arima Y. Prospects for new lung cancer treatments that target EMT signaling. Dev Dyn. 2018;247:462–72.
Andrew DJ, Ewald AJ. Morphogenesis of epithelial tubes: Insights into tube formation, elongation, and elaboration. Dev Biol. 2010;341:34–55.
Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18:99–115.
Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett. 2012;586:1959–70.
Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, et al. New insights into TGF-beta/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018;292:76–83.
Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73.
Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q, Qin J, et al. The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell. 2006;124:381–92.
Li X, Amazit L, Long W, Lonard DM, Monaco JJ, O’Malley BW. Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REGgamma-proteasome pathway. Mol Cell. 2007;26:831–42.
Chen X, Barton LF, Chi Y, Clurman BE, Roberts JM. Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol Cell. 2007;26:843–52.
Okamura T, Taniguchi S, Ohkura T, Yoshida A, Shimizu H, Sakai M, et al. Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. J Clin Endocrinol Metab. 2003;88:1374–83.
Wang X, Tu S, Tan J, Tian T, Ran L, Rodier JF, et al. REG gamma: a potential marker in breast cancer and effect on cell cycle and proliferation of breast cancer cell. Med Oncol. 2011;28:31–41.
Li L, Dang Y, Zhang J, Yan W, Zhai W, Chen H, et al. REGgamma is critical for skin carcinogenesis by modulating the Wnt/beta-catenin pathway. Nat Commun. 2015;6:6875.
Wang Q, Gao X, Yu T, Yuan L, Dai J, Wang W, et al. REGgamma controls Hippo signaling and reciprocal NF-kappaB-YAP regulation to promote colon cancer. Clin Cancer Res. 2018;24:2015–25.
He J, Cui L, Zeng Y, Wang G, Zhou P, Yang Y, et al. REGgamma is associated with multiple oncogenic pathways in human cancers. BMC Cancer. 2012;12:75.
Liu J, Wang Y, Li L, Zhou L, Wei H, Zhou Q, et al. Site-specific acetylation of the proteasome activator REGgamma directs its heptameric structure and functions. J Biol Chem. 2013;288:16567–78.
Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–8.
Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH. Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene. 2005;24:8277–90.
Tang YN, Ding WQ, Guo XJ, Yuan XW, Wang DM, Song JG. Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis. Nat Commun. 2015;6:8230.
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–8.
Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-beta-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010;29:6485–98.
Dong S, Jia C, Zhang S, Fan G, Li Y, Shan P, et al. The REGgamma proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab. 2013;18:380–91.
Xu J, Zhou L, Ji L, Chen F, Fortmann K, Zhang K, et al. The REGgamma-proteasome forms a regulatory circuit with IkappaBvarepsilon and NFkappaB in experimental colitis. Nat Commun. 2016;7:10761.
Mallini P, Lennard T, Kirby J, Meeson A. Epithelial-to-mesenchymal transition: what is the impact on breast cancer stem cells and drug resistance. Cancer Treat Rev. 2014;40:341–8.
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16:488–94.
Li L, Zhao D, Wei H, Yao L, Dang Y, Amjad A, et al. REGgamma deficiency promotes premature aging via the casein kinase 1 pathway. Proc Natl Acad Sci USA. 2013;110:11005–10.
Wang J, Lu Y, Koch AE, Zhang J, Taichman RS. CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. Cancer Res. 2008;68:10367–76.
Liu J, Yu G, Zhao Y, Zhao D, Wang Y, Wang L, et al. REGgamma modulates p53 activity by regulating its cellular localization. J Cell Sci. 2010;123:4076–84.
David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-beta tumor suppression through a lethal EMT. Cell. 2016;164:1015–30.
Ali A, Wang Z, Fu J, Ji L, Liu J, Li L, et al. Differential regulation of the REGgamma-proteasome pathway by p53/TGF-beta signalling and mutant p53 in cancer cells. Nat Commun. 2013;4:2667.
Miyazawa K, Miyazono K. Regulation of TGF-beta Family Signaling by Inhibitory Smads. Cold Spring Harb Perspect Biol. 2017;9:1–25.
Gronroos E, Hellman U, Heldin CH, Ericsson J. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell. 2002;10:483–93.
Simonsson M, Heldin CH, Ericsson J, Gronroos E. The balance between acetylation and deacetylation controls Smad7 stability. J Biol Chem. 2005;280:21797–803.
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.
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Conceptualization: LL, SS, TW, LP, PZ, GC, TH, KL, QL, SX. Supervision: LT, QH, and JF. Writing—original draft: LL, XY, and XL. Writing—review and editing: LL, REM [5], and XL.
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Tong, L., Shen, S., Huang, Q. et al. Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis. Cell Death Differ 27, 1795–1806 (2020). https://doi.org/10.1038/s41418-019-0459-6
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DOI: https://doi.org/10.1038/s41418-019-0459-6
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