Abstract
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.
Highlights
Head and neck squamous cell cancer (HNSCC) is a heterogeneous disease that potentially involves multiple sites and cellular origins within the head and neck region [1]
Enhancer of Zeste homologue 2 (EZH2) mRNA expression levels were determined in 110 HNSCC and 68 adjacent normal mucosal tissues with an independent set
EZH2 mRNA levels were significantly greater in HNSCC tissues than in adjacent normal tissues (p = 0.003) (Figure 1A)
Summary
Head and neck squamous cell cancer (HNSCC) is a heterogeneous disease that potentially involves multiple sites and cellular origins within the head and neck region [1]. Studies are required to shift their focus from prognostic biomarkers and to the development of predictive biomarkers enabling patient selection for a specific therapy [3,4]. In HNSCC, epigenomic inactivation linked to tumor suppressor genes (TSGs) are more frequent than somatic mutations in cancer and may be driving tumorigenic initiation and progression [5]. Aberrant gene promoter methylation is a key event in cancer pathogenesis and has gained increasing interest in basic and translational oncology studies because of their reversible nature [6,7]. Molecular classification of HNSCCs is required to establish prognostic and potentially preventive targets of tumor recurrence in patients
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