Research Papers:

Human papillomavirus dysregulates the cellular apparatus controlling the methylation status of H3K27 in different human cancers to consistently alter gene expression regardless of tissue of origin

Steven F. Gameiro, Bart Kolendowski, Ali Zhang, John W. Barrett, Anthony C. Nichols, Joe Torchia and Joe S. Mymryk _

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Oncotarget. 2017; 8:72564-72576. https://doi.org/10.18632/oncotarget.19885

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Steven F. Gameiro1,*, Bart Kolendowski2,*, Ali Zhang1, John W. Barrett3, Anthony C. Nichols3,4,5, Joe Torchia2,4,5 and Joe S. Mymryk1,3,4,5

1Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 3K7, Canada

2Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada

3Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON N6A 3K7, Canada

4Department of Oncology, The University of Western Ontario, London, ON N6A 3K7, Canada

5London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada

*These authors have contributed equally to this work

Correspondence to:

Joe S. Mymryk, email: [email protected]

Keywords: cancer, human papillomavirus, epigenetics, gene expression, methylation

Received: April 13, 2017    Accepted: July 03, 2017    Published: August 03, 2017


High-risk human papillomaviruses (HPV) cause cancer at multiple distinct anatomical locations. Regardless of the tissue of origin, most HPV positive (HPV+) cancers show highly upregulated expression of the p16 product of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene. Paradoxically, HPV+ tumor cells require continuous expression of this tumor suppressor for survival. Thus, restoration of normal p16 regulation has potential therapeutic value against HPV induced cancers. Normally, p16 transcription is tightly controlled at the epigenetic level via polycomb repressive complex-mediated tri-methylation of histone 3 lysine 27 (H3K27me3). Although a mechanism by which HPV induces p16 has been proposed based on tissue culture models, it has not been extensively validated in human tumors. In this study, we used data from over 800 human cervical and head and neck tumors from The Cancer Genome Atlas (TCGA) to test this model. We determined the impact of HPV status on expression from the CDKN2A locus, the adjacent CDKN2B locus, and transcript levels of key epigenetic regulators of these loci. As expected, HPV+ tumors from both anatomical sites exhibited high levels of p16. Furthermore, HPV+ tumors expressed higher levels of KDM6A, which demethylates H3K27me3. CpG methylation of the CDKN2A locus was also consistently altered in HPV+ tumors. This data validates previous tissue culture studies and identifies remarkable similarities between the effects of HPV on gene expression and DNA methylation in both cervical and oral tumors in large human cohorts. Furthermore, these results support a model whereby HPV-mediated dysregulation of CDKN2A transcription requires KDM6A, a potentially druggable target.

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