Abstract

In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861. Tumor cells are often addicted to super-enhancer-driven oncogenes and are particularly sensitive to disruption of transcription factor binding to the enhancers. Treatment of 20861 cells with bromodomain inhibitors displaced Brd4 from the HPV integration site, greatly decreased E6/E7 transcription, and inhibited cellular proliferation. Thus, Brd4 activates viral transcription at this integration site, and strong selection for E6/E7 expression can drive the formation of a super-enhancer-like element to promote oncogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAI001223-01
Application #
9566784
Study Section
Project Start
Project End
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Budget End
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
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  Publications

McBride, Alison A; Münger, Karl (2018) Expert Views on HPV Infection. Viruses 10:
Warburton, Alix; Redmond, Catherine J; Dooley, Katharine E et al. (2018) HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. PLoS Genet 14:e1007179
McBride, Alison A (2017) Oncogenic human papillomaviruses. Philos Trans R Soc Lond B Biol Sci 372:
McBride, Alison A (2017) Playing with fire: consequences of human papillomavirus DNA replication adjacent to genetically unstable regions of host chromatin. Curr Opin Virol 26:63-68
McBride, Alison A; Warburton, Alix (2017) The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog 13:e1006211
Dooley, Katharine E; Warburton, Alix; McBride, Alison A (2016) Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes. MBio 7: