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Open AccessArticle

Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation

1
Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
2
Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
3
Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
4
Department of Otolaryngology, Tokyo Voice Center, International University of Health and Welfare, Tokyo 107-0052, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3707; https://doi.org/10.3390/ijms19123707
Received: 24 October 2018 / Revised: 9 November 2018 / Accepted: 20 November 2018 / Published: 22 November 2018
(This article belongs to the Special Issue Cancer Epigenetics 2018)
Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients. View Full-Text
Keywords: EZH2; epigenetic regulation; DZNep; tumor-related genes; head and neck cancer EZH2; epigenetic regulation; DZNep; tumor-related genes; head and neck cancer
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Mochizuki, D.; Misawa, Y.; Kawasaki, H.; Imai, A.; Endo, S.; Mima, M.; Yamada, S.; Nakagawa, T.; Kanazawa, T.; Misawa, K. Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation. Int. J. Mol. Sci. 2018, 19, 3707.

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