Transcriptional repression of E-cadherin by human papillomavirus type 16 E6

• Published in: PloS one Vol. 7; no. 11; p. e48954
• Main Authors: D'Costa, Zarina J, Jolly, Carol, Androphy, Elliot J, Mercer, Andrew, Matthews, Charles M, Hibma, Merilyn H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.11.2012; Public Library of Science (PLoS)
• Subjects: Adhesion; AML1 protein; Analysis; Binding; Biology; Cadherins - genetics; Cadherins - metabolism; Cell adhesion; Cell adhesion & migration; Deoxyribonucleic acid; DNA; DNA Methylation; DNA methyltransferase; DNA Modification Methylases - metabolism; E-cadherin; E6 protein; Enzyme Activation; Epidermis; Gene Expression Regulation; Gene silencing; Genetic aspects; HCT116 Cells; Histone deacetylase; Histone Deacetylases - metabolism; Human papillomavirus; Humans; Immune response; Immune system; Langerhans cells; Medicine; Methyltransferases; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Papillomavirus; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - metabolism; Papillomavirus infections; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Mas; Repressor Proteins - genetics; Repressor Proteins - metabolism; Repressors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sp1 protein; Transcription (Genetics); Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation; Tumors; Viruses; New Zealand; Indiana; Indianapolis Indiana
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048954

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.