Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes

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 promot...

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Autores principales:	Katharine E. Dooley, Alix Warburton, Alison A. McBride
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/62fdf0edf9774edaafaf665871e70f93
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spelling	oai:doaj.org-article:62fdf0edf9774edaafaf665871e70f932021-11-15T15:50:15ZTandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes10.1128/mBio.01446-162150-7511https://doaj.org/article/62fdf0edf9774edaafaf665871e70f932016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01446-16https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Oncogenic human papillomaviruses play an essential role in the development of cervical cancer, and growth of these cancer cells requires continued expression of the viral E6 and E7 oncogenes. Integration of the virus into the host genome often results in deregulation of E6 and E7 expression, which provides a selective growth advantage and increases genetic instability of infected cells. We show here that tandemly integrated copies of the viral genome can form a super-enhancer-like element that drives E6/E7 transcription. Targeted disruption of factors binding to this element decreases viral transcription and causes cell death. Thus, cancer cells that harbor integrated HPV could be targeted by therapeutics that disrupt super-enhancer function.Katharine E. DooleyAlix WarburtonAlison A. McBrideAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Katharine E. Dooley Alix Warburton Alison A. McBride Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
description	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. IMPORTANCE Oncogenic human papillomaviruses play an essential role in the development of cervical cancer, and growth of these cancer cells requires continued expression of the viral E6 and E7 oncogenes. Integration of the virus into the host genome often results in deregulation of E6 and E7 expression, which provides a selective growth advantage and increases genetic instability of infected cells. We show here that tandemly integrated copies of the viral genome can form a super-enhancer-like element that drives E6/E7 transcription. Targeted disruption of factors binding to this element decreases viral transcription and causes cell death. Thus, cancer cells that harbor integrated HPV could be targeted by therapeutics that disrupt super-enhancer function.
format	article
author	Katharine E. Dooley Alix Warburton Alison A. McBride
author_facet	Katharine E. Dooley Alix Warburton Alison A. McBride
author_sort	Katharine E. Dooley
title	Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
title_short	Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
title_full	Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
title_fullStr	Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
title_full_unstemmed	Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
title_sort	tandemly integrated hpv16 can form a brd4-dependent super-enhancer-like element that drives transcription of viral oncogenes
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/62fdf0edf9774edaafaf665871e70f93
work_keys_str_mv	AT katharineedooley tandemlyintegratedhpv16canformabrd4dependentsuperenhancerlikeelementthatdrivestranscriptionofviraloncogenes AT alixwarburton tandemlyintegratedhpv16canformabrd4dependentsuperenhancerlikeelementthatdrivestranscriptionofviraloncogenes AT alisonamcbride tandemlyintegratedhpv16canformabrd4dependentsuperenhancerlikeelementthatdrivestranscriptionofviraloncogenes
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Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes

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