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.

Transcriptional Suppression of E-Cadherin by HPV-16 E6 and E7 Oncogenes is Independent of Hypermethylation of E-Cadherin Promoter

“…This finding is similar to that of a previous study showing that the HPV-16 E6 protein induces E-cadherin repression and that the E-cadherin promoter is repressed in cells expressing E6, causing reduced E-cadherin transcription (26).…”

“…Moreover, HPV-16 E6-expressing cells show a greater reduction in E-cadherin expression than HPV-16 E7-expressing cells, and our data suggest that HPV-16 E6 is es-sential for reducing E-cadherin expression and inducing EMT (26).…”

Epithelial-to-Mesenchymal Transition in Penile Squamous Cell Carcinoma

“…Our results are in accord with those of previous in vitro studies showing that E7 and E6 HPV proteins may trigger E-cadherin down-regulation in keratinocyte cultures. 19 HPV induced loss of E-cadherin expression in PSCC could also be due to HPV related loss of chromosome 16q, which harbors the E-cadherin gene, as reported in oral squamous cell carcinoma. 20 In contrast, we found no association between HPV and EMT.…”

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

“…E- cadherin is reduced in both high and low grade lesions in vivo as well as in vitro organotypic models 154,293,294,296,297,322,323 . High risk E6 and E7 downregulate E-cadherin and do so through several mechanisms 42,151,156,158,296,324,325 . Downregulation of E-cadherin is also seen in lesions caused by low risk HPV types 297 .…”