Other interesting genes methylated kinase inhibitors of signaling pathways in head and neck cancer include EDNRB, a member of the G protein-coupled receptor family that encodes endothelin receptor type B protein; EDNRB is methylated in 97% of primary HNSCC tissues[174]. EDNRB is involved in the development and function of blood vessels, cellular growth and mitosis[174]. Another gene methylated in HNSCC is RARB, which encodes retinoic acid receptor beta and restricts cell growth by altering gene expression. Hypermethylation of RARB results in loss of function and reduced control of transcription[154,162,163,167,175,176]. Currently, only a few methylated genes can predict the clinical outcome of HNSCC

patients. It is unknown how methylated genes correlate with cancer therapy, patient response and tumor progression and behavior. Methylation analysis techniques have revealed that methylation patterns are not affected by external factors and are increased during cancer progression. Therefore, as with stem cell surface markers, increased sensitivity and specificity of quantitative methodologies for DNA methylation analyses will allow scientists to develop prognostic tools for clinical evaluation of head and neck cancer. Histone methylation in HNSCC: Mancuso et

al[177] showed that the level of H3K4 methylation is significantly different in normal mucosa compared to oral squamous cell carcinoma (OSCC) tissues, with dimethylated K4 increased and trimethylated K4 decreased. A similar trend was observed in oral leukoplakias compared to the pathological sample[177]. H3K9 and H3K27 are targets for methylation by enhancer of

zeste homolog 2 (EZH2), a member of the Polycomb-group family, resulting in gene silencing via chromatin condensation[178-181]. Interestingly, overexpression of EZH2 is associated with malignancy and prognosis of a variety of cancers, including breast[182,183], prostate[184-186], gastric[187], hepatic[188], bladder[189,190] and oral squamous cell carcinoma[129,191]. Wei et al showed that increased expression of EZH2 is associated with dysplasia and malignant transformation. Similarly, Kidani et al[191] revealed that overexpression of EZH2 Dacomitinib is associated with tumor progression, malignancy and poor prognosis in OSCC. Collectively, these data reveal that different histone methylation patterns can greatly influence gene expression in cancer, thereby affecting malignant behavior. Histone acetylation in HNSCC: Early evidence suggested that histones and their modifiers are involved in sophisticated processes that modulate tumor behavior and cellular phenotype. We recently reported that chromatin folding in HNSCC during tumor response to environmental cues dynamically modulates tumor behavior and cellular phenotype[151]. We found that HNSCC cell lines are hypoacetylated compared to normal mucosa controls (Figure ​(Figure1A).1A).