Journal
EPIGENETICS
Volume 6, Issue 6, Pages 777-787Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/epi.6.6.16216
Keywords
epigenetics; human papillomavirus; HNSCC; DNA methylation; squamous cell carcinoma; gene expression; microarrays; illumina infinium humanmethylation27 beadarray
Funding
- University of Michigan School of Public Health (SPH)
- SPH Department of Environmental Health Sciences
- National Institute of Environmental Health Sciences [T32 ES07062]
- NIH-NIDCR [R01 DE019126]
- NIH NCI NIDCR SPORE [P50 CA097248]
- NIH-NCI Comprehensive Cancer Center [P30 CA46592]
- NIH NIDCD [P30 DC05188]
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Oncogenic human papillomaviruses (HPV) are associated with nearly all cervical cancers and are increasingly important in the etiology of oropharyngeal tumors. HPV-associated head and neck squamous cell carcinomas (HNSCC) have distinct risk profiles and appreciate a prognostic advantage compared to HPV-negative HNSCC. Promoter hypermethylation is widely recognized as a mechanism in the progression of HNSCC, but the extent to which this mechanism is consistent between HPV(+) and HPV(-) tumors is unknown. To investigate the epigenetic regulation of gene expression in HPV-induced and carcinogen-induced cancers, we examined genome-wide DNA methylation and gene expression in HPV(+) and HPV(-) SCC cell lines. We used two platforms: the Illumina Infinium Methylation BeadArray and tiling arrays, and confirmed illustrative examples with pyrosequencing and quantitative PCR. These analyses indicate that HPV(+) cell lines have higher DNA methylation in genic and LINE-1 regions than HPV(-) cell lines. Differentially methylated loci between HPV(+) and HPV(-) cell lines significantly correlated with HPV-typed HNSCC primary tumor DNA methylation levels. Novel findings include higher promoter methylation of polycomb repressive complex 2 target genes in HPV(+) cells compared to HPV(-) cells and increased expression of DNMT3A in HPV(+) cells. Additionally, CDKN2A and KRT8 were identified as interaction hubs among genes with higher methylation and lower expression in HPV(-) cells. Conversely, RUNX2, IRS-1 and CCNA1 were major hubs with higher methylation and lower expression in HPV(+) cells. Distinct HPV(+) and HPV(-) epigenetic profiles should provide clues to novel targets for development of individualized therapeutic strategies.
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