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

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
7
Issue
11
Identifiers
DOI: 10.1371/journal.pone.0048954
Source
Legacy
Keywords
  • Research Article
  • Biology
  • Microbiology
  • Virology
  • Viral Classification
  • Dna Viruses
  • Viral Immune Evasion
  • Viruses And Cancer
  • Host-Pathogen Interaction
  • Molecular Cell Biology
  • Cell Adhesion
  • Cadherins
  • Gene Expression
  • Dna Transcription
  • Medicine
  • Infectious Diseases
  • Sexually Transmitted Diseases
  • Human Papillomavirus Infection
Disciplines
  • Biology

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.

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