{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T03:07:19Z","timestamp":1778900839140,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program, National Cancer Institute.","award":["Intramural Research Program, National Cancer Institute."],"award-info":[{"award-number":["Intramural Research Program, National Cancer Institute."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions.<\/jats:p>","DOI":"10.3390\/cancers13205241","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T01:23:46Z","timestamp":1634693026000},"page":"5241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"Kyunghee","family":"Burkitt","sequence":"first","affiliation":[{"name":"Head and Neck Medical Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vassiliki","family":"Saloura","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrg816","article-title":"The fundamental role of epigenetic events in cancer","volume":"3","author":"Jones","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","article-title":"Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1470-2045(05)70540-4","article-title":"Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma","volume":"7","author":"Ha","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10238-017-0467-0","article-title":"DNA methylation profiles in cancer diagnosis and therapeutics","volume":"18","author":"Pan","year":"2018","journal-title":"Clin. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1056\/NEJMra072067","article-title":"Epigenetics in cancer","volume":"358","author":"Esteller","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/j.1442-2050.2011.01199.x","article-title":"Effects of DNA methyltransferase 1 inhibition on esophageal squamous cell carcinoma","volume":"24","author":"Zhao","year":"2011","journal-title":"Dis. Esophagus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/carcin\/bgi361","article-title":"DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas","volume":"27","author":"Peng","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/ijc.11127","article-title":"Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas","volume":"105","author":"Saito","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.oraloncology.2010.11.006","article-title":"Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa","volume":"47","author":"Paluszczak","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00784-016-1772-9","article-title":"Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients","volume":"21","author":"Supic","year":"2017","journal-title":"Clin. Oral Investig."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, L.H., Hsu, W.L., Tseng, Y.J., Liu, D.W., and Weng, C.F. (2016). Involvement of DNMT 3B promotes epithelial-mesenchymal transition and gene expression profile of invasive head and neck squamous cell carcinomas cell lines. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2468-x"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Viet, C.T., Dang, D., Achdjian, S., Ye, Y., Katz, S.G., and Schmidt, B.L. (2014). Decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112880"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.ijrobp.2008.10.032","article-title":"A systematic assessment of radiation dose enhancement by 5-Aza-2\u2019-deoxycytidine and histone deacetylase inhibitors in head-and-neck squamous cell carcinoma","volume":"73","author":"Kimpe","year":"2009","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7276","DOI":"10.1158\/1078-0432.CCR-17-1438","article-title":"Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer","volume":"23","author":"Biktasova","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1200\/JCO.2002.04.117","article-title":"Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B","volume":"20","author":"Silverman","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/cncr.21792","article-title":"Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study","volume":"106","author":"Kantarjian","year":"2006","journal-title":"Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/cr.2011.22","article-title":"Regulation of chromatin by histone modifications","volume":"21","author":"Bannister","year":"2011","journal-title":"Cell Res"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.oraloncology.2012.05.024","article-title":"Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent\/metastatic head and neck cancer","volume":"48","author":"Haigentz","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1158\/1078-0432.CCR-13-2235","article-title":"A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors","volume":"20","author":"Gray","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s10637-018-0696-4","article-title":"A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma","volume":"37","author":"Teknos","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1158\/1078-0432.CCR-19-2214","article-title":"A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer","volume":"26","author":"Rodriguez","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_23","first-page":"1155","article-title":"Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers","volume":"14","author":"Mak","year":"2020","journal-title":"Ecancermedicalscience"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Caponigro, F., Di Gennaro, E., Ionna, F., Longo, F., Aversa, C., Pavone, E., Maglione, M.G., Di Marzo, M., Muto, P., and Cavalcanti, E. (2016). Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and\/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2957-y"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1158\/1078-0432.CCR-14-2820","article-title":"A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma","volume":"21","author":"Galloway","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"576946","DOI":"10.3389\/fcell.2020.576946","article-title":"The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy","volume":"8","author":"Li","year":"2020","journal-title":"Front. Cell. Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Giudice, F.S., Pinto, D.S., Nor, J.E., Squarize, C.H., and Castilho, R.M. (2013). Inhibition of histone deacetylase impacts cancer stem cells and induces epithelial-mesenchyme transition of head and neck cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058672"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/his.13218","article-title":"Hypoacetylation of acetyl-histone H3 (H3K9ac) as marker of poor prognosis in oral cancer","volume":"71","author":"Webber","year":"2017","journal-title":"Histopathology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.fob.2013.12.003","article-title":"NFkappaB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC)","volume":"4","author":"Almeida","year":"2014","journal-title":"FEBS Open Bio"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1476-4598-7-24","article-title":"Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitizes head and neck cancer cells to cisplatin","volume":"7","author":"Burkitt","year":"2008","journal-title":"Mol. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"169","DOI":"10.18632\/genesandcancer.54","article-title":"Suberoylanilide hydroxamic acid (SAHA) reverses chemoresistance in head and neck cancer cells by targeting cancer stem cells via the downregulation of nanog","volume":"6","author":"Kumar","year":"2015","journal-title":"Genes Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13046-019-1080-8","article-title":"Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis","volume":"38","author":"He","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"732","DOI":"10.3389\/fcell.2020.00732","article-title":"Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance","volume":"8","author":"Iannelli","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.juro.2007.03.109","article-title":"Down-regulation of HLA class I antigens in prostate cancer tissues and up-regulation by histone deacetylase inhibition","volume":"178","author":"Kitamura","year":"2007","journal-title":"J. Urol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7017","DOI":"10.4049\/jimmunol.165.12.7017","article-title":"Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors","volume":"165","author":"Magner","year":"2000","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1158\/2326-6066.CIR-15-0077-T","article-title":"HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade","volume":"3","author":"Woods","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1073\/pnas.1011037108","article-title":"Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies","volume":"108","author":"Christiansen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7390","DOI":"10.18632\/oncotarget.7180","article-title":"Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells","volume":"7","author":"Gameiro","year":"2016","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4259","DOI":"10.1002\/cncr.28356","article-title":"Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma","volume":"119","author":"Chen","year":"2013","journal-title":"Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.oraloncology.2008.03.016","article-title":"High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas","volume":"45","author":"Kidani","year":"2009","journal-title":"Oral Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1002\/cncr.26575","article-title":"Up-regulation of enhancer of zeste homolog 2 is associated positively with cyclin D1 overexpression and poor clinical outcome in head and neck squamous cell carcinoma","volume":"118","author":"Cao","year":"2012","journal-title":"Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.bbrc.2016.09.055","article-title":"EZH2 promotes invasion and metastasis of laryngeal squamous cells carcinoma via epithelial-mesenchymal transition through H3K27me3","volume":"479","author":"Luo","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/mc.21848","article-title":"Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma","volume":"52","author":"Wang","year":"2013","journal-title":"Mol. Carcinog."},{"key":"ref_44","first-page":"1165","article-title":"Targeting of EZH2 inhibits epithelialmesenchymal transition in head and neck squamous cell carcinoma via regulating the STAT3\/VEGFR2 axis","volume":"55","author":"Zhao","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.oraloncology.2015.11.002","article-title":"EZH2 is associated with poor prognosis in head-and-neck squamous cell carcinoma via regulating the epithelial-to-mesenchymal transition and chemosensitivity","volume":"52","author":"Chang","year":"2016","journal-title":"Oral Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3892\/ol.2016.4704","article-title":"EZH2 is overexpressed in laryngeal squamous cell carcinoma and enhances the stem-like properties of AMC-HN-8 cells","volume":"12","author":"Huang","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1158\/1078-0432.CCR-19-1351","article-title":"Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer","volume":"26","author":"Zhou","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_48","unstructured":"(2021, May 05). Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/b-cell.pdf."},{"key":"ref_49","unstructured":"(2021, September 06). Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/sarcoma.pdf."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Majchrzak-Celinska, A., Warych, A., and Szoszkiewicz, M. (2021). Novel Approaches to Epigenetic Therapies: From Drug Combinations to Epigenetic Editing. Genes, 12.","DOI":"10.3390\/genes12020208"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5241\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:17:56Z","timestamp":1760167076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,19]]},"references-count":50,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cancers13205241"],"URL":"https:\/\/doi.org\/10.3390\/cancers13205241","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,19]]}}}