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5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers
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 i...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672859/ https://www.ncbi.nlm.nih.gov/pubmed/33203436 http://dx.doi.org/10.1186/s13148-020-00965-8 |
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author | 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. |
author_facet | 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. |
author_sort | Liu, Siyu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7672859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-76728592020-11-19 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. Clin Epigenetics Research 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. BioMed Central 2020-11-17 /pmc/articles/PMC7672859/ /pubmed/33203436 http://dx.doi.org/10.1186/s13148-020-00965-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research 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. 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title | 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title_full | 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title_fullStr | 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title_full_unstemmed | 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title_short | 5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
title_sort | 5-hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672859/ https://www.ncbi.nlm.nih.gov/pubmed/33203436 http://dx.doi.org/10.1186/s13148-020-00965-8 |
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