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5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers.
Liu, Siyu; de Medeiros, Marcell Costa; Fernandez, Evan M; Zarins, Katie R; Cavalcante, Raymond G; Qin, Tingting; Wolf, Gregory T; Figueroa, Maria E; D'Silva, Nisha J; Rozek, Laura S; Sartor, Maureen A.
Afiliación
  • Liu S; Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA.
  • de Medeiros MC; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, 48104, USA.
  • Fernandez EM; Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA.
  • Zarins KR; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Cavalcante RG; Epigenomics Core, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Qin T; Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA.
  • Wolf GT; Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, MI, 48109, USA.
  • Figueroa ME; Department of Human Genetics and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
  • D'Silva NJ; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, 48104, USA.
  • Rozek LS; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Sartor MA; Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA. sartorma@umich.edu.
Clin Epigenetics ; 12(1): 175, 2020 11 17.
Article en En | MEDLINE | ID: mdl-33203436
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 cancer-related 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Papillomaviridae / Queratinocitos / 5-Metilcitosina / Carcinoma de Células Escamosas de Cabeza y Cuello / Uniones Intercelulares Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies Límite: Female / Humans / Male / Middle aged Idioma: En Revista: Clin Epigenetics Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Papillomaviridae / Queratinocitos / 5-Metilcitosina / Carcinoma de Células Escamosas de Cabeza y Cuello / Uniones Intercelulares Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies Límite: Female / Humans / Male / Middle aged Idioma: En Revista: Clin Epigenetics Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania