Novel Epigenetic Modifiers of Histones Presenting Potent Inhibitory Effects on Adenoid Cystic Carcinoma Stemness and Invasive Properties.

Adenoid cystic carcinoma (ACC) is a rare neoplasm known for its indolent clinical course, risk of perineural invasion, and late onset of distant metastasis. Due to the scarcity of samples and the tumor's rarity, progress in developing effective treatments has been historically limited. To tackle this issue, a high-throughput screening of epigenetic drugs was conducted to identify compounds capable of disrupting the invasive properties of the tumor and its cancer stem cells (CSCs). ACC cells were screened for changes in tumor viability, chromatin decondensation, Snail inhibition along tumor migration, and disruption of cancer stem cells. Seven compounds showed potential clinical interest, and further validation showed that Scriptaid emerged as a promising candidate for treating ACC invasion. Scriptaid demonstrated a favorable cellular toxicity index, effectively inhibited Snail expression, induced hyperacetylation of histone, reduced cell migration, and effectively disrupted tumorspheres. Additionally, LMK235 displayed encouraging results in four out of five validation assays, further highlighting its potential in combating tumor invasion in ACC. By targeting the invasive properties of the tumor and CSCs, Scriptaid and LMK235 hold promise as potential treatments for ACC, with the potential to improve patient outcomes and pave the way for further research in this critical area.

Using PDX animal models to identify and stratify adenoid cystic carcinoma patients presenting an enhanced response to HDAC inhibitors.

Adenoid cystic carcinoma (ACC) patients face a highly infiltrative and metastatic disease characterized by poor survival rates and suboptimal response to available therapies. We have previously shown that sensitization of ACC tumors to chemotherapy using histone deacetylase inhibitors (HDACi) constitutes a promising therapeutic strategy to manage tumor growth. Here, we used patient-derived xenografts (PDX) from ACC tumors to evaluate the effects of in vivo administration of the HDAC inhibitor Entinostat combined with Cisplatin over tumor growth. RNA from PDX tumor samples receiving the proposed therapy were analyzed using NanoString technology to identify molecular signatures capable of predicting ACC response to the therapy. We also used an RNAseq dataset from 68 ACC patients to validate the molecular signature identified by the NanoString platform. We found that the administration of Entinostat combined with Cisplatin resulted in a potent tumor growth inhibition (TGI) ranging from 38% to 106% of the original tumor mass. Enhanced response to therapy is consistent with the reactivation of tumor suppressor genes, including SFRP1, and the downregulation of oncogenes like FGF8 and CCR7. Nanostring data from PDX tumors identified a genetic signature capable of predicting tumor response to therapy. We further stratified 68 ACC patients containing RNAseq data accordingly to the activity levels of the identified genetic signature. We found that 23% of all patients exhibit a genetic signature consistent with a high ACC tumor response rate to Entinostat and Cisplatin. Our study provides compelling preclinical data supporting the deployment of a powerful systemic anticancer therapy crafted and explicitly tested for ACC tumors.

Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFκB and histone deacetylation inhibition.

Despite many progresses in the development of new systemic therapies for oral squamous cell carcinoma (OSCC), the five-year survival rate of OSCC is low. The traditional chemotherapies approach (cisplatin - CDDP) shows some limitations like drug toxicity, limited efficacy, and drug resistance. Promising studies suggested OSCC cancer stem cells (CSC) presented resistance to CDDP. We have previously studied many targets, and we extensively showed the efficacy of the NFκB signaling and the role of histones acetylation, on different malignant tumors, including adenoid cystic carcinoma and mucoepidermoid carcinoma, but until then the effects of the NFkB inhibitor and histone deacetylase (HDAC) inhibitor on the biology of OSCC were not evaluated. Here we assessed the pharmacological inhibitor of NFκB emetine and HDAC inhibitor SAHA on the behavior of CSC derived from OSCC. Our data suggested that CDDP administration resulted in reduced viability of bulk OSCC cells and increased CSC. A single and isolated shot of emetine and SAHA were able to disrupt CSC by inhibiting the NFκB pathway and increasing the histone acetylation levels, respectively. Further, the combined administration of emetine and SAHA presented the same CSC disruption as seen in emetine alone.

Adenoid Cystic Carcinoma from the salivary and lacrimal glands and the breast: Different clinical outcomes to the same tumor.

Adenoid cystic carcinoma (ACC) is a biphasic malignant lesion that can develop at various anatomical sites. Salivary and lacrimal ACC lesions have a high risk of local invasion, metastasis, and poor prognosis. In more distant organs, such as the breast, ACC is a rarer and less aggressive lesion. One of the major predictors of mortality of ACC is perineural invasion, which can be seen in 30 % of breast lesions, 85% of salivary lesions, and almost 100 % of lacrimal gland tumors. The biological differences between these three ACC tumors are still poorly understood. We focused on the current understanding of the genetic variations observed on ACC tumors and prognostic differences associated with distinct anatomical sites. A special effort was made to present the currently available therapies alongside the emerging strategies under development.

Histone Modification on Parathyroid Tumors: A Review of Epigenetics.

Parathyroid tumors are very prevalent conditions among endocrine tumors, being the second most common behind thyroid tumors. Secondary hyperplasia can occur beyond benign and malignant neoplasia in parathyroid glands. Adenomas are the leading cause of hyperparathyroidism, while carcinomas represent less than 1% of the cases. Tumor suppressor gene mutations such as MEN1 and CDC73 were demonstrated to be involved in tumor development in both familiar and sporadic types; however, the epigenetic features of the parathyroid tumors are still a little-explored subject. We present a review of epigenetic mechanisms related to parathyroid tumors, emphasizing advances in histone modification and its perspective of becoming a promising area in parathyroid tumor research.

From Tissue Physoxia to Cancer Hypoxia, Cost-Effective Methods to Study Tissue-Specific O2 Levels in Cellular Biology.

The human body is endowed with an extraordinary ability to maintain different oxygen levels in various tissues and organs. The maintenance of physiological levels of oxygen is known as physoxia. The development of hypoxic conditions plays an important role in the biology of several pathologies, including cancer. In vitro studies using normal and neoplastic cells require that culture conditions be carried out under appropriate oxygen levels, either physoxic or hypoxic conditions. Such requirements are difficult to widely implement in laboratory practice, mainly due to the high costs of specialized equipment. In this work, we present and characterize a cost-effective method to culture cells under a range of oxygen levels using deoxidizing pouches. Our results show that physoxic and hypoxic levels using deoxidizing absorbers can be achieved either by implementing a gradual change in oxygen levels or by a regimen of acute depletion of oxygen. This approach triggers the activation of an epithelial-mesenchymal transition in cancer cells while stimulating the expression of HIF-1α. Culturing cancer cells with deoxidizing agent pouches revealed PI3K oncogenic pathway exacerbations compared to tumor cells growing under atmospheric levels of oxygen. Similar to the PI3K signaling disturbance, we also observed augmented oxidative stress and superoxide levels and increased cell cycle arrest. Most interestingly, the culture of cancer cells under hypoxia resulted in the accumulation of cancer stem cells in a time-dependent manner. Overall, we present an attractive, cost-effective method of culturing cells under appropriate physoxic or hypoxic conditions that is easily implementable in any wet laboratory equipped with cell culture tools.

Periodontal disease affects oral cancer progression in a surrogate animal model for tobacco exposure.

For decades, the link between poor oral hygiene and the increased prevalence of oral cancer has been suggested. Most recently, emerging evidence has suggested that chronic inflammatory diseases from the oral cavity (e.g., periodontal disease), to some extent, play a role in the development of oral squamous cell carcinoma (OSCC). The present study aimed to explore the direct impact of biofilm­induced periodontitis in the carcinogenesis process using a tobacco surrogate animal model for oral cancer. A total of 42 Wistar rats were distributed into four experimental groups: Control group, periodontitis (Perio) group, 4­nitroquinoline 1­oxide (4­NQO) group and 4NQO/Perio group. Periodontitis was stimulated by placing a ligature subgingivally, while oral carcinogenesis was induced by systemic administration of 4NQO in the drinking water for 20 weeks. It was observed that the Perio, 4NQO and 4NQO/Perio groups presented with significantly higher alveolar bone loss compared with that in the control group. Furthermore, all groups receiving 4NQO developed lesions on the dorsal surface of the tongue; however, the 4NQO/Perio group presented larger lesions compared with the 4NQO group. There was also a modest overall increase in the number of epithelial dysplasia and OSCC lesions in the 4NQO/Perio group. Notably, abnormal focal activation of cellular differentiation (cytokeratin 10­positive cells) that extended near the basal cell layer of the mucosa was observed in rats receiving 4NQO alone, but was absent in rats receiving 4NQO and presenting with periodontal disease. Altogether, the presence of periodontitis combined with 4NQO administration augmented tumor size in the current rat model and tampered with the protective mechanisms of the cellular differentiation of epithelial cells.

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

AIM: To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands. MATERIAL AND METHODS: UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation. RESULTS: A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity. CONCLUSION: Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.

Oral health care professionals recommending and administering the HPV vaccine: Understanding the strengths and assessing the barriers.

INTRODUCTION: Head and neck cancer is a deadly cancer that ranks among the six most common cancers worldwide. The HPV vaccine has been used to prevent head and neck cancer of the oropharynx, and changes in health policies and state law are impacting the role of dental professionals in HPV vaccination. However, relatively little is known about dental professionals' attitudes regarding the vaccine. OBJECTIVES: Our study assesses dental professionals' willingness to administer the HPV vaccine, their confidence discussing HPV with patients, beliefs about the vaccine's efficacy, perceived barriers to administering it, and sites of referral. METHODS: We surveyed 623 dental professionals, including dentists, hygienists, dental students, and hygiene students across Michigan. Attitudes toward the vaccine and predictive characteristics were evaluated by logistic regression, ANOVAs, and t-tests. RESULTS: The majority of the respondents (51% of dentists, 63% of hygienists, 82% of dental students, and 71% of hygiene students) were willing to administer the HPV vaccine if allowed by law. The role of dental and dental hygiene students would be one of advocacy, educating and recommending the vaccine, and the dental students administering it once licensed. Dental professionals were variably confident discussing HPV with patients and generally believed it enhanced patients' health. Stronger confidence and beliefs were associated with greater willingness to administer the vaccine. Barriers among professionals opposing the HPV vaccine included lack of knowledge on the subject, liability concerns, and personal beliefs. CONCLUSION: Dental professionals can become leaders in preventing HPV-related cancers. Training and continuing education courses could enhance their confidence and willingness to recommend and administer the HPV vaccine. POLICY IMPLICATIONS: Legislation that permits dental professionals to administer the vaccine could increase the vaccine's accessibility to patients, improve vaccination rates, and population health.

Entinostat is a novel therapeutic agent to treat oral squamous cell carcinoma.

INTRODUCTION: Alterations of the epigenome may influence cancer initiation and progression. At the cellular level, histones are key regulators of chromatin accessibility and gene transcription; thus, the inhibition of histone deacetylase enzymes (HDACs) constitutes an attractive target for therapy. In this study, we investigated the effects of the HDAC inhibitor entinostat on oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: We tested the effects of entinostat on OSCC cell lines. Cell viability and growth were analyzed using MTT assay. Cell cycle analysis, cell apoptosis, cancer stem cell (CSC) content, and the concentration of reactive oxygen species (ROS) in OSCC tumor cells were assessed using flow cytometry. The expression of histones and cell cycle regulatory proteins was examined by Western blot. RESULTS: The administration of entinostat resulted in reduced proliferation of OSCC cells, followed by cell cycle arrest at the G0/G1 phase, as well as substantial tumor apoptosis. We found an increase in ROS production and significant reductions in CSCs. We also found that entinostat caused increased acetylation histone H3 and histone H4, and changes in the expression of cell cycle-associated proteins such as p21. CONCLUSION: This study indicates that entinostat is a potential novel therapeutic agent for OSCC by halting tumor proliferation, inducing cytotoxicity and intracellular ROS, and attacking the CSCs.

Pharmacological PTEN inhibition: potential clinical applications and effects in tissue regeneration.

Although the human body can heal, it takes time, and slow healing and chronic wounds often occur. Thus, identifying novel therapies to aid regeneration is needed. Here, we conducted a systematic review following the Preferred Reporting Items for Systematic Reviews guidelines and assessed preclinical studies on phosphatase and tensin homolog (PTEN) inhibitors and their effects on tissue repair and regeneration. In conditions associated with neurodegeneration, tissue injury and ischemia, the PTEN-regulated PI3K/AKT signaling pathway is activated. The use of PTEN inhibitors resulted in better tissue response by reducing the healing time and lesion sizes or inducing neuronal regeneration. Notably, all studies included in this systematic review indicated that pharmacological inhibition of PTEN enhanced the repair process of the eye, lung, muscle and nervous system.

Asparaginase induces selective dose- and time-dependent cytotoxicity, apoptosis, and reduction of NFκB expression in oral cancer cells.

Asparaginase is fundamental to the treatment of haematological malignancies. However, little has been studied on the effects that asparaginase could exert on solid tumours. Thus, this study aimed to evaluate the effects of asparaginase on an oral carcinoma cell line. The cytotoxicity of asparaginase in SCC-9 (tongue squamous cell carcinoma) and HaCaT (human keratinocyte) cell lines was evaluated with MTT cell viability assay. The cells were treated with asparaginase at 0.04, 0.16, 0.63, 1.0, 1.5, 2.5, and 5.0 IU/mL. Dose-response curves and IC50 values were obtained and the Tumour Selectivity Index (TSI) was calculated. The effect of asparaginase on procaspase-3 and nuclear factor κB (NFκB) expression was evaluated with western blot because it was reported that the overexpression of NFκB has been shown to contribute to tumour cell survival, proliferation, and migration. Caspase 3/7 staining was performed to identify cell death using flow cytometry. Effective asparaginase concentrations were lower for SCC-9 cells when compared to HaCaT cells. The cytotoxicity results at 48 and 72 hours were significantly different for SCC-9 cells. The TSI indicated that asparaginase was selective for the tumour cells. A decrease in procaspase-3 and NFκB protein levels was observed in SCC-9 cells. Furthermore, asparaginase resulted in significant apoptosis after 48 and 72 hours. Based on these results, asparaginase was cytotoxic in a dose- and time-dependent manner, induces apoptosis, and reduces NFκB expression in oral cancer cells. These results encourage further studies on the effectiveness of this enzyme as a treatment for solid tumours, especially head and neck cancer.

Characterization of macrophages infiltrating peri-implantitis lesions.

OBJECTIVES: The mechanisms involved in the initiation and progression of peri-implantitis lesions are poorly understood. It was the aim to determine the content and activation status of macrophages present in human peri-implantitis lesions and compare the current findings with the macrophage polarization associated with periodontitis lesions. MATERIAL AND METHODS: A total of 14 patients were studied in this investigation. Seven were soft tissue biopsies from dental implants affected by peri-implantitis that required explantation. Seven biopsies were from chronic periodontal disease. Immunofluorescence stains were performed using biomarkers to identify macrophages (CD68+ ) undergoing M1 polarization (iNOS+ ) and M2 polarization (CD206+ ), along with Hoechst 33,342 to identify DNA content. All samples were stained and photographed, and double-positive cells for CD68 and iNOS or CD68 and CD206 were quantified. RESULTS: All peri-implantitis biopsies examined revealed a mixed population of macrophages undergoing M1 polarization and M2 polarization. Further analysis demonstrated the co-expression of iNOS and CD206, which indicates the presence of a heterogenic immune response on peri-implantitis lesions. Macrophage polarization in peri-implantitis lesions presents a distinct pattern than in periodontitis. We observed a significant increase in the population of M1 macrophages on peri-implantitis samples compared to periodontal disease samples. CONCLUSION: Our results demonstrate that peri-implantitis has higher numbers of macrophages displaying a distinct macrophage M1 polarization signature compared to periodontitis lesions. This pattern may explain, in part, the distinct nature of peri-implantitis progression vs. periodontitis in humans.

Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide and is characterized by a fast-paced growth. Like other solid tumors, the HNSCC growth rate results in the development of hypoxic regions identified by the expression of hypoxia-inducible factor 1α (HIF-1α). Interestingly, clinical data have shown that pharmacological induction of intratumoral hypoxia caused an unexpected rise in tumor metastasis and the accumulation of cancer stem cells (CSCs). However, little is known on the molecular circuitries involved in the presence of intratumoral hypoxia and the augmented population of CSCs. Here we explore the impact of hypoxia on the behavior of HNSCC and define that the controlling function of phosphatase and tensin homolog (PTEN) over HIF-1α expression and CSC accumulation are de-regulated during hypoxic events. Our findings indicate that hypoxic niches are poised to accumulate CSCs in a molecular process driven by the loss of PTEN activity. Furthermore, our data suggest that targeted therapies aiming at the PTEN/PI3K signaling may constitute an effective strategy to counteract the development of intratumoral hypoxia and the accumulation of CSCs.-Nascimento-Filho, C. H. V., Webber, L. P., Borgato, G. B., Goloni-Bertollo, E. M., Squarize, C. H., Castilho, R. M. Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN.

Interference with the bromodomain epigenome readers drives p21 expression and tumor senescence.

Head and neck cancer (HNSCC) are one of the most common solid malignancies of the world, being responsible for over 350,000 deaths every year. Much of the complications in managing and treating HNSCC advent from the complex genetic and epigenetic landscape of the disease. Emerging information has shown promising results in targeting BRD4, an epigenetic regulator bromodomain that functions as a scaffold for transcription factors at promoters and super-enhancers. Here we show that by disrupting the interaction between BRD4 and histones using the bromodomain inhibitor JQ1, HNSCC cells undergo cell growth arrest followed by cellular senescence. Mechanistically, JQ1 negatively impacted the phosphorylation levels of SIRT1 along with the acetylation levels of mutant p53 (active). In vivo administration of JQ1 resulted in disruption of HNSCC growth along with the activation of cellular senescence, observed by the accumulation of DNA double-strand breaks, p16ink4, accumulation of senescence-associated beta-galactosidase, and loss of phosphorylated Sirt1ser47. Furthermore, we also demonstrate that JQ1 was efficient in reducing the population of cancer stem cells from HNSCC xenografts.

Characterization of macrophage polarization in periodontal disease.

AIM: To explore the M1/M2 status of macrophage polarization from healthy, gingivitis, and periodontitis patient samples. MATERIALS AND METHODS: Gingival biopsies were collected from 42 individuals (14 gingivitis, 18 periodontitis, and 10 healthy samples) receiving periodontal therapy. Histomorphology analysis was performed with haematoxylin and eosin staining. Immunofluorescence was performed using a combination of CD68 (macrophages), iNOS (M1), and CD206 (M2) in order to acquire changes in macrophage polarization at a single-cell resolution. Macrophages were quantified under microscopy using narrow wavelength filters to detect Alexa 488, Alexa 568, Alexa 633 fluorophores, and Hoechst 33342 to identify cellular DNA content. RESULTS: Gingivitis and periodontitis samples showed higher levels of macrophages compared with healthy samples. Unexpectedly, periodontitis samples displayed lower levels of macrophages dispersed in the stromal tissues compared with gingivitis samples; however, it remained higher than healthy tissues. The polarization of macrophages appears to be reduced in periodontitis and showed similar levels to those observed in healthy tissues. CONCLUSIONS: Our study found that gingivitis and periodontitis differ from each other by the levels of macrophage infiltrate, but not by changes in macrophage polarization.

Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma.

PURPOSE: Emerging evidence indicates that bromodomains comprise a conserved class of epigenome readers involved in cancer development and inflammation. Bromodomains are associated with epigenetic modifications of gene transcription through interactions with lysine residues of histone tails. Particularly, the bromodomain and extra-terminal domain (BET) family member BRD4 has been found to be involved in the control over oncogenes, including c-MYC, and in the maintenance of downstream inflammatory processes. The objective of this study was to evaluate the effect of pharmacologically displacing BRD4 in mucoepidermoid carcinoma (MEC) cells. METHODS: We assessed the presence of BRD4 levels in a panel of human MEC tissue samples in conjunction with histological grading and clinical information. In vitro studies were carried out using human MEC-derived cell lines. The BET inhibitor iBET762 was administered to MEC cells to assess the impact of disrupted BRD4 signaling on colony forming capacities and cell cycle status. The activation of cellular senescence induced by iBET762 was determined by immunohistochemical staining for p16ink4. Flow cytometry was used to identify populations of cancer stem cells in MEC-derived cell lines. RESULTS: We found that primary human MECs and MEC-derived cell lines are endowed with high BRD4 expression levels compared to those in normal salivary glands. We also found that, by displacing BRD4 from chromatin using the BET inhibitor iBET762, MEC cells lose their colony forming capacities and undergo G1 cell cycle arrest and senescence. Finally, we found that targeted displacement of BRD4 from chromatin results in depletion of cancer stem cells from the overall MEC cell populations. CONCLUSIONS: Our findings indicate that bromodomain-mediated gene regulation constitutes an epigenetic mechanism that is deregulated in MEC cells and that the use of BET inhibitors may serve as a feasible therapeutic strategy to manage MECs.

Targeting histone deacetylase and NFκB signaling as a novel therapy for Mucoepidermoid Carcinomas.

Malignancies from the salivary glands are rare and represent 11% of all cancers from the oropharyngeal anatomical area. Mucoepidermoid Carcinomas (MEC) is the most common malignancy from the salivary glands. Low survival rates of high-grade Mucoepidermoid Carcinomas (MEC) are particularly associated with the presence of positive lymph nodes, extracapsular lymph node spread, and perineural invasion. Most recently, the presence of cancer stem cells (CSC), and the activation of the NFκB signaling pathway have been suggested as cues for an acquired resistance phenotype. We have previously shown that NFκB signaling is very active in MEC tumors. Herein, we explore the efficacy of NFκB inhibition in combination with class I and II HDAC inhibitor to deplete the population of CSC and to destroy MEC tumor cells. Our finding suggests that disruption of NFκB signaling along with the administration of HDAC inhibitors constitute an effective strategy to manage MEC tumors.

Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy.

Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.