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Article

DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression

  • Authors:
    • Jerome Perrard
    • Adrien Morel
    • Koceila Meznad
    • Philippe Paget‑Bailly
    • Veronique Dalstein
    • David Guenat
    • Celine Mourareau
    • Christine Clavel
    • Sylvie Fauconnet
    • Aurelie Baguet
    • Christiane Mougin
    • Jean‑Luc Pretet
  • View Affiliations / Copyright

    Affiliations: Équipe d'Accueil 3181, University of Bourgogne Franche‑Comté, Laboratoire d'Excellence Lipoprotéines et Santé, Prévention et Traitement des Maladies Inflammatoires et du Cancer, 25000 Besançon, France, Center For Research in Genetics and Genomics‑CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 112041, Colombia, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche‑S 1250 Pathologies Pulmonaires et Plasticité Cellulaire, Université de Reims Champagne‑Ardenne, Faculté de Médecine, 51000 Reims, France
  • Pages: 1074-1081
    |
    Published online on: November 28, 2019
       https://doi.org/10.3892/ol.2019.11158
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Abstract

HPV16 is the most carcinogenic human papillomavirus and causes >50% of cervical cancers, the majority of anal cancers and 30% of oropharyngeal squamous cell carcinomas. HPV carcinogenesis relies on the continuous expression of the two main viral oncoproteins E6 and E7 that target >150 cellular proteins. Among them, epigenetic modifiers, including DNA Methyl Transferases (DNMT), are dysregulated, promoting an aberrant methylation pattern in HPV‑positive cancer cells. It has been previously reported that the treatment of HPV‑positive cervical cancer cells with DNMT inhibitor 5‑aza‑2'‑deoxycytidine (5azadC) caused the downregulation of E6 expression due to mRNA destabilization that was mediated by miR‑375. Recently, the T‑box transcription factor 2 (TBX2) has been demonstrated to repress HPV LCR activity. In the current study, the role of TBX2 in E6 repression was investigated in HPV16 cervical cancer cell lines following 5azadC treatment. A decrease of E6 expression was accompanied by p53 and p21 restoration. While TBX2 mRNA was upregulated in 5azadC‑treated SiHa and Ca Ski cells, TBX2 protein was not detectable. Furthermore, the overexpression of TBX2 protein in cervical cancer cells did not allow the repression of E6 expression. The TBX2 transcription factor is therefore unlikely to be associated with the repression of E6 following 5azadC treatment of SiHa and Ca Ski cells.
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1 

Doorbar J, Egawa N, Griffin H, Kranjec C and Murakami I: Human papillomavirus molecular biology and disease association. Rev Med Virol. 25 (Suppl 1):S2–S23. 2015. View Article : Google Scholar

2 

Scheffner M, Werness BA, Huibregtse JM, Levine AJ and Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 63:1129–1136. 1990. View Article : Google Scholar : PubMed/NCBI

3 

Münger K, Scheffner M, Huibregtse JM and Howley PM: Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv. 12:197–217. 1992.PubMed/NCBI

4 

Huh K, Zhou X, Hayakawa H, Cho JY, Libermann TA, Jin J, Harper JW and Munger K: Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor. J Virol. 81:9737–9747. 2007. View Article : Google Scholar : PubMed/NCBI

5 

zur Hausen H: Human papillomaviruses in the pathogenesis of anogenital cancer. Virology. 184:9–13. 1991. View Article : Google Scholar : PubMed/NCBI

6 

Jacquin E, Baraquin A, Ramanah R, Carcopino X, Morel A, Valmary-Degano S, Bravo IG, de Sanjosé S, Riethmuller D, Mougin C and Prétet JL: Methylation of human papillomavirus Type 16 CpG sites at E2-binding site 1 (E2BS1), E2BS2, and the Sp1-binding site in cervical cancer samples as determined by high-resolution melting analysis-PCR. J Clin Microbiol. 51:3207–3215. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Zhang C, Deng Z, Pan X, Uehara T, Suzuki M and Xie M: Effects of methylation status of CpG sites within the HPV16 long control region on HPV16-positive head and neck cancer cells. PLoS One. 10:e01412452015. View Article : Google Scholar : PubMed/NCBI

8 

Stich M, Ganss L, Puschhof J, Prigge ES, Reuschenbach M, Guiterrez A, Vinokurova S and von Knebel Doeberitz M: 5-aza-2′-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene expression and blocks neoplastic growth of HPV-associated cancer cells. Oncotarget. 8:52104–52117. 2016.PubMed/NCBI

9 

Morel A, Baguet A, Perrard J, Demeret C, Jacquin E, Guenat D, Mougin C and Prétet JL: 5azadC treatment upregulates miR-375 level and represses HPV16 E6 expression. Oncotarget. 8:46163–46176. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Jung HM, Phillips BL and Chan EK: miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ. Mol Cancer. 13:802014. View Article : Google Scholar : PubMed/NCBI

11 

Schneider MA, Scheffer KD, Bund T, Boukhallouk F, Lambert C, Cotarelo C, Pflugfelder GO, Florin L and Spoden GA: The transcription factors TBX2 and TBX3 interact with human papillomavirus 16 (HPV16) L2 and repress the long control region of HPVs. J Virol. 87:4461–4474. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Wansleben S, Peres J, Hare S, Goding CR and Prince S: T-box transcription factors in cancer biology. Biochim Biophys Acta. 1846:380–391. 2014.PubMed/NCBI

13 

Abrahams A, Parker MI and Prince S: The T-box transcription factor Tbx2: Its role in development and possible implication in cancer. IUBMB Life. 62:92–102. 2010.PubMed/NCBI

14 

Du WL, Fang Q, Chen Y, Teng JW, Xiao YS, Xie P, Jin B and Wang JQ: Effect of silencing the T-Box transcription factor TBX2 in prostate cancer PC3 and LNCaP cells. Mol Med Rep. 16:6050–6058. 2017. View Article : Google Scholar : PubMed/NCBI

15 

Khalil A, Dekmak B, Boulos F, Kantrowitz J, Spira A, Fujimoto J, Kadara H, El-Hachem N and Nemer G: Transcriptomic alterations in lung adenocarcinoma unveil new mechanisms targeted by the TBX2 subfamily of tumor suppressor genes. Front Oncol. 8:4822018. View Article : Google Scholar : PubMed/NCBI

16 

Khalil AA, Sivakumar S, Lucas FAS, McDowell T, Lang W, Tabata K, Fujimoto J, Yatabe Y, Spira A, Scheet P, et al: TBX2 subfamily suppression in lung cancer pathogenesis: A high-potential marker for early detection. Oncotarget. 8:68230–68241. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Rani L, Mathur N, Gupta R, Gogia A, Kaur G, Dhanjal JK, Sundar D, Kumar L and Sharma A: Genome-wide DNA methylation profiling integrated with gene expression profiling identifiesPAX9as a novel prognostic marker in chronic lymphocytic leukemia. Clin Epigenetics. 9:572017. View Article : Google Scholar : PubMed/NCBI

18 

Farkas SA, Sorbe BG and Nilsson TK: Epigenetic changes as prognostic predictors in endometrial carcinomas. Epigenetics. 12:19–26. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Kandimalla R, van Tilborg AA, Kompier LC, Stumpel DJ, Stam RW, Bangma CH and Zwarthoff EC: Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers. Eur Urol. 61:1245–1256. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Gangat N, Patnaik MM and Tefferi A: Myelodysplastic syndromes: Contemporary review and how we treat. Am J Hematol. 91:76–89. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Nieto M, Demolis P, Béhanzin E, Moreau A, Hudson I, Flores B, Stemplewski H, Salmonson T, Gisselbrecht C, Bowen D and Pignatti F: The european medicines agency review of decitabine (Dacogen) for the treatment of adult patients with acute myeloid leukemia: Summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 21:692–700. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Biktasova A, Hajek M, Sewell A, Gary C, Bellinger G, Deshpande HA, Bhatia A, Burtness B, Judson B, Mehra S, et al: Demethylation therapy as a targeted treatment for human papillomavirus-associated head and neck cancer. Clin Cancer Res. 23:7276–7287. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Prince S, Carreira S, Vance KW, Abrahams A and Goding CR: Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Cancer Res. 64:1669–1674. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM, van Welsem T, van de Vijver MJ, Koh EY, Daley GQ and van Lohuizen M: Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet. 26:291–299. 2000. View Article : Google Scholar : PubMed/NCBI

26 

Vance KW, Carreira S, Brosch G and Goding CR: Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res. 65:2260–2268. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Harrelson Z, Kelly RG, Goldin SN, Gibson-Brown JJ, Bollag RJ, Silver LM and Papaioannou VE: Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development. 131:5041–5052. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Lüdtke TH, Rudat C, Wojahn I, Weiss AC, Kleppa MJ, Kurz J, Farin HF, Moon A, Christoffels VM and Kispert A: Tbx2 and Tbx3 act downstream of shh to maintain canonical wnt signaling during branching morphogenesis of the murine lung. Dev Cell. 39:239–253. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Zhu B, Zhang M, Williams EM, Keller C, Mansoor A and Davie JK: TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle. Oncogene. 35:4212–4224. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Redmond KL, Crawford NT, Farmer H, D'Costa ZC, O'Brien GJ, Buckley NE, Kennedy RD, Johnston PG, Harkin DP and Mullan PB: T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells. Oncogene. 29:3252–3262. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Perrard J, Morel A, Meznad K, Paget‑Bailly P, Dalstein V, Guenat D, Mourareau C, Clavel C, Fauconnet S, Baguet A, Baguet A, et al: DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression. Oncol Lett 19: 1074-1081, 2020.
APA
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D. ... Pretet, J. (2020). DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression. Oncology Letters, 19, 1074-1081. https://doi.org/10.3892/ol.2019.11158
MLA
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D., Mourareau, C., Clavel, C., Fauconnet, S., Baguet, A., Mougin, C., Pretet, J."DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression". Oncology Letters 19.1 (2020): 1074-1081.
Chicago
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D., Mourareau, C., Clavel, C., Fauconnet, S., Baguet, A., Mougin, C., Pretet, J."DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression". Oncology Letters 19, no. 1 (2020): 1074-1081. https://doi.org/10.3892/ol.2019.11158
Copy and paste a formatted citation
x
Spandidos Publications style
Perrard J, Morel A, Meznad K, Paget‑Bailly P, Dalstein V, Guenat D, Mourareau C, Clavel C, Fauconnet S, Baguet A, Baguet A, et al: DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression. Oncol Lett 19: 1074-1081, 2020.
APA
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D. ... Pretet, J. (2020). DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression. Oncology Letters, 19, 1074-1081. https://doi.org/10.3892/ol.2019.11158
MLA
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D., Mourareau, C., Clavel, C., Fauconnet, S., Baguet, A., Mougin, C., Pretet, J."DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression". Oncology Letters 19.1 (2020): 1074-1081.
Chicago
Perrard, J., Morel, A., Meznad, K., Paget‑Bailly, P., Dalstein, V., Guenat, D., Mourareau, C., Clavel, C., Fauconnet, S., Baguet, A., Mougin, C., Pretet, J."DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression". Oncology Letters 19, no. 1 (2020): 1074-1081. https://doi.org/10.3892/ol.2019.11158
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