title: Transcriptional repression of E-cadherin by human papillomavirus type 16 E6.
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.
authors.affiliation: Virus Research Unit, Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
authors.forename: Zarina J
authors.initials: ZJ
authors.lastname: D'Costa
authors.forename: Carol
authors.initials: C
authors.lastname: Jolly
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.forename: Andrew
authors.initials: A
authors.lastname: Mercer
authors.forename: Charles M
authors.initials: CM
authors.lastname: Matthews
authors.forename: Merilyn H
authors.initials: MH
authors.lastname: Hibma
mesh_terms: D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D015820:Cadherins; C068651:E6 protein, Human papillomavirus type 16; C000715470:MAS1 protein, human; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; C059731:oncogene protein E7, Human papillomavirus type 16; D015254:DNA Modification Methylases; D006655:Histone Deacetylases