Transcriptional Repression of E-Cadherin by Human Papillomavirus Type 16 E6

Zarina J. D'Costa, Carol Jolly, Elliot J. Androphy, Andrew Mercer, Charles M. Matthews, Merilyn H. Hibma

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Abstract

There is increasing evidence supporting DNA virus regulation of the cell adhesion and tumour suppressor protein, E-cadherin. We previously reported that loss of E-cadherin in human papillomavirus (HPV) type 16-infected epidermis is contributed to by the major viral proto-oncogene E6 and is associated with reduced Langerhans cells density, potentially regulating the immune response. The focus of this study is determining how the HPV16 E6 protein mediates E-cadherin repression. We found that the E-cadherin promoter is repressed in cells expressing E6, resulting in fewer E-cadherin transcripts. On exploring the mechanism for this, repression by increased histone deacetylase activity or by increased binding of trans-repressors to the E-cadherin promoter Epal element was discounted. In contrast, DNA methyltransferase (DNMT) activity was increased in E6 expressing cells. Upon inhibiting DNMT activity using 5-Aza-2′-deoxycytidine, E-cadherin transcription was restored in the presence of HPV16 E6. The E-cadherin promoter was not directly methylated, however a mutational analysis showed general promoter repression and reduced binding of the transactivators Sp1 and AML1 and the repressor Slug. Expression of E7 with E6 resulted in a further reduction in surface E-cadherin levels. This is the first report of HPV16 E6-mediated transcriptional repression of this adhesion molecule and tumour suppressor protein.

Original languageEnglish (US)
Article numbere48954
JournalPLoS ONE
Volume7
Issue number11
DOIs
StatePublished - Nov 26 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

D'Costa, Z. J., Jolly, C., Androphy, E. J., Mercer, A., Matthews, C. M., & Hibma, M. H. (2012). Transcriptional Repression of E-Cadherin by Human Papillomavirus Type 16 E6. PLoS ONE, 7(11), [e48954]. https://doi.org/10.1371/journal.pone.0048954