5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers
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RESEARCH
5‑Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers Siyu Liu1, Marcell Costa de Medeiros2, Evan M. Fernandez1, Katie R. Zarins3, Raymond G. Cavalcante4, Tingting Qin1, Gregory T. Wolf5, Maria E. Figueroa6, Nisha J. D’Silva2, Laura S. Rozek3 and Maureen A. Sartor1,7*
Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied. Results: We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines. Conclusion: Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancerrelated processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups. Keywords: Head and neck cancer, Human papillomavirus, Hydroxymethylation Background Head and neck squamous cell carcinoma (HNSCC) includes tumors in the oral cavity, larynx and oropharynx, and is the sixth most prevalent cancer worldwide [1, 2]. Globally, HNSCC affects approximately 680,000 *Correspondence: [email protected] 1 Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI 48109‑2218, USA Full list of author information is available at the end of the article
patients every year, with a five-year survival rate ranging from 37 to 62% [3]. While tobacco and alcohol consumption are long-recognized risk factors, high-risk strains of human papillomavirus (HPV), in particular HPV-16, account for an increasing number of cases [4]. HPV(+) HNSCC patients generally show better therapeutic response, improve
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