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Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation

Authors: Wenlu Li, Dandan Zhu, Shuaihua Qin

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. The epithelial-to-mesenchymal transition (EMT) is crucial for increasing the metastasis of OSCC. Recently, studies have indicated that sirtuin7 (SIRT7) is implicated in tumor genesis; however, the potential role of SIRT7 in the EMT and metastasis of OSCC has not been reported.

Methods

We investigated the cellular responses to SIRT7 silencing or overexpression in OSCC cell lines by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry.

Results

In the present study, we found that SIRT7 was significantly downregulated in OSCC cell lines and human OSCC/OSCC tissues with lymph node metastasis. Overexpression of SIRT7 decreased the proliferation and invasion of OSCC cells in vitro, whereas SIRT7 knockdown significantly increased OSCC cell growth and invasion. Upregulation of SIRT7 concomitantly increased the expression of E-cadherin, and decreased the expression of mesenchymal markers. SIRT7 overexpression also reduced the level of acetylated SMAD4 in OSCC cells. Moreover, SIRT7 overexpression significantly inhibited OSCC lung metastasis in vivo.

Conclusion

Together, these findings suggested that SIRT7 suppressed EMT in OSCC metastasis by promoting SMAD4 deacetylation.
Literature
1.
go back to reference Xie T, Li X, Ye F, Lu C, Huang H, Wang F, Cao X, Zhong C. High KIF2A expression promotes proliferation, migration and predicts poor prognosis in lung adenocarcinoma. Biochem Biophys Res Commun. 2018;497:65–72.CrossRefPubMed Xie T, Li X, Ye F, Lu C, Huang H, Wang F, Cao X, Zhong C. High KIF2A expression promotes proliferation, migration and predicts poor prognosis in lung adenocarcinoma. Biochem Biophys Res Commun. 2018;497:65–72.CrossRefPubMed
2.
go back to reference Li B, Chen M, Lu M, Xin-Xiang J, Meng-Xiong P, Jun-Wu M. Glutaredoxin 3 promotes migration and invasion via the notch signalling pathway in oral squamous cell carcinoma. Free Radic Res. 2018:1–12. Li B, Chen M, Lu M, Xin-Xiang J, Meng-Xiong P, Jun-Wu M. Glutaredoxin 3 promotes migration and invasion via the notch signalling pathway in oral squamous cell carcinoma. Free Radic Res. 2018:1–12.
3.
go back to reference Yang H, Pan L, Xu C, Zhang Y, Li K, Chen S, Zhang B, Liu Z, Wang LX, Chen H. Overexpression of tumor suppressor gene ZNF750 inhibits oral squamous cell carcinoma metastasis. Oncol Lett. 2017;14:5591–6.PubMedPubMedCentral Yang H, Pan L, Xu C, Zhang Y, Li K, Chen S, Zhang B, Liu Z, Wang LX, Chen H. Overexpression of tumor suppressor gene ZNF750 inhibits oral squamous cell carcinoma metastasis. Oncol Lett. 2017;14:5591–6.PubMedPubMedCentral
4.
go back to reference Rao SJ, Rao JBM, Rao PJ. Immunohistochemical analysis of stromal fibrocytes and myofibroblasts to envision the invasion and lymph node metastasis in oral squamous cell carcinoma. J Oral Maxillofac Pathol. 2017;21:218–23.CrossRefPubMedPubMedCentral Rao SJ, Rao JBM, Rao PJ. Immunohistochemical analysis of stromal fibrocytes and myofibroblasts to envision the invasion and lymph node metastasis in oral squamous cell carcinoma. J Oral Maxillofac Pathol. 2017;21:218–23.CrossRefPubMedPubMedCentral
5.
go back to reference Zidar N, Bostjancic E, Malgaj M, Gale N, Dovsak T, Didanovic V. The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity. Virchows Arch. 2017; Zidar N, Bostjancic E, Malgaj M, Gale N, Dovsak T, Didanovic V. The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity. Virchows Arch. 2017;
6.
go back to reference Wang SH, Chang JS, Hsiao JR, Yen YC, Jiang SS, Liu SH, Chen YL, Shen YY, Chang JY, Chen YW. Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial-mesenchymal transition of lymphatic endothelial cells. Oncogene. 2017;36:1503–15.CrossRefPubMed Wang SH, Chang JS, Hsiao JR, Yen YC, Jiang SS, Liu SH, Chen YL, Shen YY, Chang JY, Chen YW. Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial-mesenchymal transition of lymphatic endothelial cells. Oncogene. 2017;36:1503–15.CrossRefPubMed
7.
go back to reference MR DEA, Perez-Sayans M, Suarez-Penaranda JM, Somoza-Martin JM, Garcia-Garcia A. p27(Kip1) expression as a prognostic marker for squamous cell carcinoma of the head and neck. MR DEA, Perez-Sayans M, Suarez-Penaranda JM, Somoza-Martin JM, Garcia-Garcia A. p27(Kip1) expression as a prognostic marker for squamous cell carcinoma of the head and neck.
8.
go back to reference Li Z, Liu J, Li L, Shao S, Wu J, Bian L, He Y. Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma. Oncol Rep. 2018;39:1356–68.PubMed Li Z, Liu J, Li L, Shao S, Wu J, Bian L, He Y. Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma. Oncol Rep. 2018;39:1356–68.PubMed
9.
go back to reference Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H, Dang CV, Le AD. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget. 2017;8:9557–71.PubMed Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H, Dang CV, Le AD. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget. 2017;8:9557–71.PubMed
10.
go back to reference Tamura T, Ichikawa T, Nakahata S, Kondo Y, Tagawa Y, Yamamoto K, Nagai K, Baba T, Yamaguchi R, Futakuchi M, et al. Loss of NDRG2 expression confers oral squamous cell carcinoma with enhanced metastatic potential. Cancer Res. 2017;77:2363–74.CrossRefPubMed Tamura T, Ichikawa T, Nakahata S, Kondo Y, Tagawa Y, Yamamoto K, Nagai K, Baba T, Yamaguchi R, Futakuchi M, et al. Loss of NDRG2 expression confers oral squamous cell carcinoma with enhanced metastatic potential. Cancer Res. 2017;77:2363–74.CrossRefPubMed
11.
go back to reference Kim SE, Shin SH, Lee JY, Kim CH, Chung IK, Kang HM, Park HR, Park BS, Kim IR. Resveratrol induces mitochondrial apoptosis and inhibits epithelial-Mesenchymal transition in oral squamous cell carcinoma cells. Nutr Cancer. 2018;70:125–35.CrossRefPubMed Kim SE, Shin SH, Lee JY, Kim CH, Chung IK, Kang HM, Park HR, Park BS, Kim IR. Resveratrol induces mitochondrial apoptosis and inhibits epithelial-Mesenchymal transition in oral squamous cell carcinoma cells. Nutr Cancer. 2018;70:125–35.CrossRefPubMed
12.
go back to reference Wang H, Deng X, Zhang J, Ou Z, Mai J, Ding S, Huo S. Elevated expression of zinc finger protein 703 promotes cell proliferation and metastasis through PI3K/AKT/GSK-3beta Signalling in oral squamous cell carcinoma. Cell Physiol Biochem. 2017;44:920–34.CrossRefPubMed Wang H, Deng X, Zhang J, Ou Z, Mai J, Ding S, Huo S. Elevated expression of zinc finger protein 703 promotes cell proliferation and metastasis through PI3K/AKT/GSK-3beta Signalling in oral squamous cell carcinoma. Cell Physiol Biochem. 2017;44:920–34.CrossRefPubMed
13.
go back to reference Schwock J, Bradley G, Ho JC, Perez-Ordonez B, Hedley DW, Irish JC, Geddie WR. SNAI1 expression and the mesenchymal phenotype: an immunohistochemical study performed on 46 cases of oral squamous cell carcinoma. BMC Clin Pathol. 2010;10(1) Schwock J, Bradley G, Ho JC, Perez-Ordonez B, Hedley DW, Irish JC, Geddie WR. SNAI1 expression and the mesenchymal phenotype: an immunohistochemical study performed on 46 cases of oral squamous cell carcinoma. BMC Clin Pathol. 2010;10(1)
14.
go back to reference Huber MA, Maier HJ, Alacakaptan M, Wiedemann E, Braunger J, Boehmelt G, Madwed JB, Young ER, Marshall DR, Pehamberger H, et al. BI 5700, a selective chemical inhibitor of IkappaB kinase 2, specifically suppresses epithelial-Mesenchymal transition and metastasis in mouse models of tumor progression. Genes Cancer. 2010;1:101–14.CrossRefPubMedPubMedCentral Huber MA, Maier HJ, Alacakaptan M, Wiedemann E, Braunger J, Boehmelt G, Madwed JB, Young ER, Marshall DR, Pehamberger H, et al. BI 5700, a selective chemical inhibitor of IkappaB kinase 2, specifically suppresses epithelial-Mesenchymal transition and metastasis in mouse models of tumor progression. Genes Cancer. 2010;1:101–14.CrossRefPubMedPubMedCentral
15.
go back to reference Lu M, Wang C, Chen W, Mao C, Wang J. miR-654-5p targets GRAP to promote proliferation, metastasis, and Chemoresistance of oral squamous cell carcinoma through Ras/MAPK signaling. DNA Cell Biol. 2018; Lu M, Wang C, Chen W, Mao C, Wang J. miR-654-5p targets GRAP to promote proliferation, metastasis, and Chemoresistance of oral squamous cell carcinoma through Ras/MAPK signaling. DNA Cell Biol. 2018;
16.
go back to reference Chung MK, Jung YH, Lee JK, Cho SY, Murillo-Sauca O, Uppaluri R, Shin JH, Sunwoo JB. CD271 confers an invasive and metastatic phenotype of head and neck squamous cell carcinoma through the Upregulation of slug. Clin Cancer Res. 2018;24:674–83.CrossRefPubMed Chung MK, Jung YH, Lee JK, Cho SY, Murillo-Sauca O, Uppaluri R, Shin JH, Sunwoo JB. CD271 confers an invasive and metastatic phenotype of head and neck squamous cell carcinoma through the Upregulation of slug. Clin Cancer Res. 2018;24:674–83.CrossRefPubMed
17.
go back to reference Zhu G, Wang S, Chen J, Wang Z, Liang X, Wang X, Jiang J, Lang J, Li L. Long noncoding RNA HAS2-AS1 mediates hypoxia-induced invasiveness of oral squamous cell carcinoma. Mol Carcinog. 2017;56:2210–22.CrossRefPubMed Zhu G, Wang S, Chen J, Wang Z, Liang X, Wang X, Jiang J, Lang J, Li L. Long noncoding RNA HAS2-AS1 mediates hypoxia-induced invasiveness of oral squamous cell carcinoma. Mol Carcinog. 2017;56:2210–22.CrossRefPubMed
18.
go back to reference Chen IC, Chiang WF, Huang HH, Chen PF, Shen YY, Chiang HC. Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis. Mol Cancer. 2014;13:254.CrossRefPubMedPubMedCentral Chen IC, Chiang WF, Huang HH, Chen PF, Shen YY, Chiang HC. Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis. Mol Cancer. 2014;13:254.CrossRefPubMedPubMedCentral
19.
go back to reference Li D, Li L. MicroRNA3666 inhibits breast cancer cell proliferation by targeting sirtuin 7. Mol Med Rep. 2017;16:8493–500.CrossRefPubMed Li D, Li L. MicroRNA3666 inhibits breast cancer cell proliferation by targeting sirtuin 7. Mol Med Rep. 2017;16:8493–500.CrossRefPubMed
20.
go back to reference Lee HS, Jung W, Lee E, Chang H, Choi JH, Kim HG, Kim A, Kim BH. SIRT7, H3K18ac, and ELK4 Immunohistochemical expression in hepatocellular carcinoma. J Pathol Transl Med. 2016;50:337–44.CrossRefPubMedPubMedCentral Lee HS, Jung W, Lee E, Chang H, Choi JH, Kim HG, Kim A, Kim BH. SIRT7, H3K18ac, and ELK4 Immunohistochemical expression in hepatocellular carcinoma. J Pathol Transl Med. 2016;50:337–44.CrossRefPubMedPubMedCentral
21.
go back to reference Li W, Sun Z, Chen C, Wang L, Geng Z, Tao J. Sirtuin7 has an oncogenic potential via promoting the growth of cholangiocarcinoma cells. Biomed Pharmacother. 2018;100:257–66.CrossRefPubMed Li W, Sun Z, Chen C, Wang L, Geng Z, Tao J. Sirtuin7 has an oncogenic potential via promoting the growth of cholangiocarcinoma cells. Biomed Pharmacother. 2018;100:257–66.CrossRefPubMed
22.
go back to reference Wei W, Jing ZX, Ke Z, Yi P. Sirtuin 7 plays an oncogenic role in human osteosarcoma via downregulating CDC4 expression. Am J Cancer Res. 2017;7:1788–803.PubMedPubMedCentral Wei W, Jing ZX, Ke Z, Yi P. Sirtuin 7 plays an oncogenic role in human osteosarcoma via downregulating CDC4 expression. Am J Cancer Res. 2017;7:1788–803.PubMedPubMedCentral
23.
go back to reference Shi H, Ji Y, Zhang D, Liu Y, Fang P. MicroRNA-3666-induced suppression of SIRT7 inhibits the growth of non-small cell lung cancer cells. Oncol Rep. 2016;36:3051–7.CrossRefPubMed Shi H, Ji Y, Zhang D, Liu Y, Fang P. MicroRNA-3666-induced suppression of SIRT7 inhibits the growth of non-small cell lung cancer cells. Oncol Rep. 2016;36:3051–7.CrossRefPubMed
24.
go back to reference Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, Xu Q, Zhou M, Cao X, Zhu WG, et al. SIRT7 antagonizes TGF-beta signaling and inhibits breast cancer metastasis. Nat Commun. 2017;8:318.CrossRefPubMedPubMedCentral Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, Xu Q, Zhou M, Cao X, Zhu WG, et al. SIRT7 antagonizes TGF-beta signaling and inhibits breast cancer metastasis. Nat Commun. 2017;8:318.CrossRefPubMedPubMedCentral
25.
go back to reference Lai CC, Lin PM, Lin SF, Hsu CH, Lin HC, Hu ML, Hsu CM, Yang MY. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 2013;34:1847–54.CrossRefPubMed Lai CC, Lin PM, Lin SF, Hsu CH, Lin HC, Hu ML, Hsu CM, Yang MY. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 2013;34:1847–54.CrossRefPubMed
26.
go back to reference Vakhrusheva O, Braeuer D, Liu Z, Braun T, Bober E. Sirt7-dependent inhibition of cell growth and proliferation might be instrumental to mediate tissue integrity during aging. J Physiol Pharmacol. 2008;59(Suppl 9):201–12.PubMed Vakhrusheva O, Braeuer D, Liu Z, Braun T, Bober E. Sirt7-dependent inhibition of cell growth and proliferation might be instrumental to mediate tissue integrity during aging. J Physiol Pharmacol. 2008;59(Suppl 9):201–12.PubMed
27.
go back to reference Palmirotta R, Cives M, Della-Morte D, Capuani B, Lauro D, Guadagni F, Silvestris F. Sirtuins and Cancer: role in the epithelial-Mesenchymal transition. Oxidative Med Cell Longev. 2016;2016:3031459.CrossRef Palmirotta R, Cives M, Della-Morte D, Capuani B, Lauro D, Guadagni F, Silvestris F. Sirtuins and Cancer: role in the epithelial-Mesenchymal transition. Oxidative Med Cell Longev. 2016;2016:3031459.CrossRef
28.
go back to reference Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X, Zhou Y, Wang H, Pan C, Huang W. Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res. 2014;20:3434–45.CrossRefPubMed Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X, Zhou Y, Wang H, Pan C, Huang W. Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res. 2014;20:3434–45.CrossRefPubMed
29.
go back to reference McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, Dickson EJ, Carter CR, McKay CJ, Shiels PG. SIRT3 & SIRT7: potential novel biomarkers for determining outcome in pancreatic Cancer patients. PLoS One. 2015;10:e0131344.CrossRefPubMedPubMedCentral McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, Dickson EJ, Carter CR, McKay CJ, Shiels PG. SIRT3 & SIRT7: potential novel biomarkers for determining outcome in pancreatic Cancer patients. PLoS One. 2015;10:e0131344.CrossRefPubMedPubMedCentral
30.
go back to reference Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen RI, Paredes S, Young NL, Chen K, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature. 2012;487:114–8.CrossRefPubMedPubMedCentral Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen RI, Paredes S, Young NL, Chen K, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature. 2012;487:114–8.CrossRefPubMedPubMedCentral
31.
go back to reference Malik S, Villanova L, Tanaka S, Aonuma M, Roy N, Berber E, Pollack JR, Michishita-Kioi E, Chua KF. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. Sci Rep. 2015;5:9841.CrossRefPubMedPubMedCentral Malik S, Villanova L, Tanaka S, Aonuma M, Roy N, Berber E, Pollack JR, Michishita-Kioi E, Chua KF. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. Sci Rep. 2015;5:9841.CrossRefPubMedPubMedCentral
32.
go back to reference Vakhrusheva O, Braeuer D Fau – Liu Z, Liu Z Fau - Braun T, Braun T Fau - Bober E, Bober E. Sirt7-dependent inhibition of cell growth and proliferation might be instrumental to mediate tissue integrity during Aging. Vakhrusheva O, Braeuer D Fau – Liu Z, Liu Z Fau - Braun T, Braun T Fau - Bober E, Bober E. Sirt7-dependent inhibition of cell growth and proliferation might be instrumental to mediate tissue integrity during Aging.
33.
go back to reference Simic P, Williams EO, Bell EL, Gong JJ, Bonkowski M, Guarente L. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep. 2013;3:1175–86.CrossRefPubMed Simic P, Williams EO, Bell EL, Gong JJ, Bonkowski M, Guarente L. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep. 2013;3:1175–86.CrossRefPubMed
34.
go back to reference Luo L, McGarvey P, Madhavan S, Kumar R, Gusev Y, Upadhyay G. Distinct lymphocyte antigens 6 (Ly6) family members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome. Oncotarget. 2016;7:11165–93.PubMedPubMedCentral Luo L, McGarvey P, Madhavan S, Kumar R, Gusev Y, Upadhyay G. Distinct lymphocyte antigens 6 (Ly6) family members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome. Oncotarget. 2016;7:11165–93.PubMedPubMedCentral
Metadata
Title
SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation
Authors
Wenlu Li
Dandan Zhu
Shuaihua Qin
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0819-y

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