Silencing DEK downregulates cervical cancer tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3β/p-Tyr216-GSK-3β/β-catenin axis

Xu,Xiaoyang; Zou,Lin; Yao,Qiuhui; Zhang,Yanbo; Gan,Li; Tang,Liangdan

doi:10.3892/or.2017.5721

Silencing DEK downregulates cervical cancer tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3β/p-Tyr216-GSK-3β/β-catenin axis

Authors:
- Xiaoyang Xu
- Lin Zou
- Qiuhui Yao
- Yanbo Zhang
- Li Gan
- Liangdan Tang
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Laboratory of Molecular Diagnosis, The Children's Hospital of Chongqing Medical University, Chongqing 400010, P.R. China, Department of Gynecology and Obstetrics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: June 14, 2017 https://doi.org/10.3892/or.2017.5721
Pages: 1035-1042

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cervical cancer is the second most common gynecological malignancy. The mechanisms of the genesis and progression of cervical cancer are complicated and not thoroughly understood. DEK is reported as an oncogene in various cancers, such as acute myeloid leukemia, bladder cancer, breast cancer and hepatocellular cancer. However, its role in cervical cancer has not been well studied. In our study, we confirmed the DEK protein as an oncoprotein in cervical cancer tissues which is correlated to cervical cancer FIGO staging and tumor type. Moreover, in vitro loss of DEK inhibited cervical cancer cell proliferation, migration and invasion. We proved that silencing DEK downregulated Wnt/β-catenin and MMP-9, and silencing DEK increased GSK-3β activity via regulating its phosphorylation instead of translation. Silencing DEK reduced p-Ser9-GSK-3β and increased p-Tyr216-GSK-3β, which resulted in β-catenin degradation. Finally, the xenograft model in nude mice proved that silencing DEK impaired cervical cancer cell tumorigenicity. This research unveiled the function of DEK in tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3β/p-Tyr216-GSK-3β/β-catenin axis in cervical cancer and gave insights into DEK-targeting therapy for patients suffering from cervical cancer.

View Figures

View References

1	Parekh N, Donohue JM, Men A, Corbelli J and Jarlenski M: Cervical Cancer Screening Guideline Adherence Before and After Guideline Changes in Pennsylvania Medicaid. Obstet Gynecol. 129:66–75. 2017. View Article : Google Scholar : PubMed/NCBI
2	Machalek DA, Wark JD, Tabrizi SN, Hopper JL, Bui M, Dite GS, Cornall AM, Pitts M, Gertig D, Erbas B, et al: Genetic and environmental factors in invasive cervical cancer: Design and methods of a classical twin study. Twin Res Hum Genet. 20:10–18. 2017. View Article : Google Scholar : PubMed/NCBI
3	Sawaya GF and Smith-McCune K: Cervical cancer screening. Obstet Gynecol. 127:459–467. 2016. View Article : Google Scholar : PubMed/NCBI
4	Knudson AG Jr: Overview: Genes that predispose to cancer. Mutat Res. 247:185–190. 1991. View Article : Google Scholar : PubMed/NCBI
5	Sandén C and Gullberg U: The DEK oncoprotein and its emerging roles in gene regulation. Leukemia. 29:1632–1636. 2015.PubMed/NCBI
6	Deutzmann A, Ganz M, Schönenberger F, Vervoorts J, Kappes F and Ferrando-May E: The human oncoprotein and chromatin architectural factor DEK counteracts DNA replication stress. Oncogene. 34:4270–4277. 2015. View Article : Google Scholar : PubMed/NCBI
7	Sandén C, Nilsson HJ and Gullberg U: The DEK oncoprotein is upregulated by multiple leukemia-associated fusion genes. Blood Cells Mol Dis. 54:284–285. 2015. View Article : Google Scholar : PubMed/NCBI
8	Liu X, Qi D, Qi J, Mao Z, Li X, Zhang J, Li J and Gao W: Significance of DEK overexpression for the prognostic evaluation of non-small cell lung carcinoma. Oncol Rep. 35:155–162. 2016.PubMed/NCBI
9	Yi HC, Liu YL, You P, Pan JS, Zhou JY, Liu ZJ and Zhang ZY: Overexpression of DEK gene is correlated with poor prognosis in hepatocellular carcinoma. Mol Med Rep. 11:1318–1323. 2015.PubMed/NCBI
10	Wise-Draper TM, Morreale RJ, Morris TA, Mintz-Cole RA, Hoskins EE, Balsitis SJ, Husseinzadeh N, Witte DP, Wikenheiser-Brokamp KA, Lambert PF, et al: DEK proto-oncogene expression interferes with the normal epithelial differentiation program. Am J Pathol. 174:71–81. 2009. View Article : Google Scholar : PubMed/NCBI
11	Martinez-Useros J, Rodriguez-Remirez M, Borrero-Palacios A, Moreno I, Cebrian A, del Gomez Pulgar T, del Puerto-Nevado L, Vega-Bravo R, Puime-Otin A, Perez N, et al: DEK is a potential marker for aggressive phenotype and irinotecan-based therapy response in metastatic colorectal cancer. BMC Cancer. 14:9652014. View Article : Google Scholar : PubMed/NCBI
12	Hu HG, Scholten I, Gruss C and Knippers R: The distribution of the DEK protein in mammalian chromatin. Biochem Biophys Res Commun. 358:1008–1014. 2007. View Article : Google Scholar : PubMed/NCBI
13	Sawatsubashi S, Murata T, Lim J, Fujiki R, Ito S, Suzuki E, Tanabe M, Zhao Y, Kimura S, Fujiyama S, et al: A histone chaperone, DEK, transcriptionally coactivates a nuclear receptor. Genes Dev. 24:159–170. 2010. View Article : Google Scholar : PubMed/NCBI
14	Liu K, Feng T, Liu J, Zhong M and Zhang S: Silencing of the DEK gene induces apoptosis and senescence in CaSki cervical carcinoma cells via the up-regulation of NF-κB p65. Biosci Rep. 32:323–332. 2012. View Article : Google Scholar : PubMed/NCBI
15	Vinnedge Privette LM, McClaine R, Wagh PK, Wikenheiser-Brokamp KA, Waltz SE and Wells SI: The human DEK oncogene stimulates β-catenin signaling, invasion and mammosphere formation in breast cancer. Oncogene. 30:2741–2752. 2011. View Article : Google Scholar : PubMed/NCBI
16	Vinnedge Privette LM, Ho SM, Wikenheiser-Brokamp KA and Wells SI: The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer. PLoS One. 7:e469852012. View Article : Google Scholar : PubMed/NCBI
17	Carro MS, Spiga FM, Quarto M, Di Ninni V, Volorio S, Alcalay M and Müller H: DEK Expression is controlled by E2F and deregulated in diverse tumor types. Cell Cycle. 5:1202–1207. 2006. View Article : Google Scholar : PubMed/NCBI
18	Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9:2431–2438. 1990.PubMed/NCBI
19	Eldar-Finkelman H: Glycogen synthase kinase 3: An emerging therapeutic target. Trends Mol Med. 8:126–132. 2002. View Article : Google Scholar : PubMed/NCBI
20	Park CH, Lee BH, Ahn SG, Yoon JH and Oh SH: Serine 9 and tyrosine 216 phosphorylation of GSK-3β differentially regulates autophagy in acquired cadmium resistance. Toxicol Sci. 135:380–389. 2013. View Article : Google Scholar : PubMed/NCBI
21	Hu Y, Gu X, Li R, Luo Q and Xu Y: Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells. J Exp Clin Cancer Res. 29:1542010. View Article : Google Scholar : PubMed/NCBI
22	He F, Chen H, Yang P, Wu Q, Zhang T, Wang C, Wei J, Chen Z, Hu H, Li W, et al: Gankyrin sustains PI3K/GSK-3β/β-catenin signal activation and promotes colorectal cancer aggressiveness and progression. Oncotarget. 7:81156–81171. 2016.PubMed/NCBI
23	Hartigan JA, Xiong WC and Johnson GV: Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Commun. 284:485–489. 2001. View Article : Google Scholar : PubMed/NCBI
24	Miyashita K, Nakada M, Shakoori A, Ishigaki Y, Shimasaki T, Motoo Y, Kawakami K and Minamoto T: An emerging strategy for cancer treatment targeting aberrant glycogen synthase kinase 3 beta. Anticancer Agents Med Chem. 9:1114–1122. 2009. View Article : Google Scholar : PubMed/NCBI
25	Cole A, Frame S and Cohen P: Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J. 377:249–255. 2004. View Article : Google Scholar : PubMed/NCBI
26	Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW and Lee CM: Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA. 97:11074–11079. 2000. View Article : Google Scholar : PubMed/NCBI
27	Hsieh CH, Hsu HH, Shibu MA, Day CH, Bau DT, Ho CC, Lin YM, Chen MC, Wang SH and Huang CY: Down-regulation of β-catenin and the associated migration ability by Taiwanin C in arecoline and 4-NQO-induced oral cancer cells via GSK-3β activation. Mol Carcinog. 56:1055–1067. 2017. View Article : Google Scholar : PubMed/NCBI
28	Hu C, Dong T, Li R, Lu J, Wei X and Liu P: Emodin inhibits epithelial to mesenchymal transition in epithelial ovarian cancer cells by regulation of GSK-3β/β-catenin/ZEB1 signaling pathway. Oncol Rep. 35:2027–2034. 2016.PubMed/NCBI
29	Fu Y, Zheng S, An N, Athanasopoulos T, Popplewell L, Liang A, Li K, Hu C and Zhu Y: β-catenin as a potential key target for tumor suppression. Int J Cancer. 129:1541–1551. 2011. View Article : Google Scholar : PubMed/NCBI
30	Gupta A, Verma A, Mishra AK, Wadhwa G, Sharma SK and Jain CK: The Wnt pathway: Emerging anticancer strategies. Recent Pat Endocr Metab Immune Drug Discov. 7:138–147. 2013. View Article : Google Scholar : PubMed/NCBI
31	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
32	Nair RR, Solway J and Boyd DD: Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J Biol Chem. 281:26424–26436. 2006. View Article : Google Scholar : PubMed/NCBI
33	Varela AT, Simões AM, Teodoro JS, Duarte FV, Gomes AP, Palmeira CM and Rolo AP: Indirubin-3′-oxime prevents hepatic I/R damage by inhibiting GSK-3beta and mitochondrial permeability transition. Mitochondrion. 10:456–463. 2010. View Article : Google Scholar : PubMed/NCBI
34	Wilson KL, Cowart CJ, Rosen BL, Pulczinski JC, Solari KD, Ory MG and Smith ML: Characteristics associated with HPV diagnosis and perceived risk for cervical cancer among unmarried, sexually active college women. J Cancer Educ. Nov 28–2016.(Epub ahead of print). View Article : Google Scholar
35	Liu S, Wang X, Sun F, Kong J, Li Z and Lin Z: DEK overexpression is correlated with the clinical features of breast cancer. Pathol Int. 62:176–181. 2012. View Article : Google Scholar : PubMed/NCBI
36	Datta A, Adelson ME, Mogilevkin Y, Mordechai E, Sidi AA and Trama JP: Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer. BMC Cancer. 11:2342011. View Article : Google Scholar : PubMed/NCBI
37	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar : PubMed/NCBI
38	Domoto T, Pyko IV, Furuta T, Miyashita K, Uehara M, Shimasaki T, Nakada M and Minamoto T: Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci. 107:1363–1372. 2016. View Article : Google Scholar : PubMed/NCBI