{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:22:31Z","timestamp":1792059751866,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["NRF-2020R1A2C1007473"],"award-info":[{"award-number":["NRF-2020R1A2C1007473"]}]},{"name":"National Research Foundation of Korea","award":["2022C100"],"award-info":[{"award-number":["2022C100"]}]},{"name":"National Research Foundation of Korea","award":["2019-0234"],"award-info":[{"award-number":["2019-0234"]}]},{"name":"National Research Foundation of Korea","award":["CRI18035-1"],"award-info":[{"award-number":["CRI18035-1"]}]},{"name":"Commercialization\u2019s Promotion Agency for R&amp;D Outcomes (COMPA)","award":["NRF-2020R1A2C1007473"],"award-info":[{"award-number":["NRF-2020R1A2C1007473"]}]},{"name":"Commercialization\u2019s Promotion Agency for R&amp;D Outcomes (COMPA)","award":["2022C100"],"award-info":[{"award-number":["2022C100"]}]},{"name":"Commercialization\u2019s Promotion Agency for R&amp;D Outcomes (COMPA)","award":["2019-0234"],"award-info":[{"award-number":["2019-0234"]}]},{"name":"Commercialization\u2019s Promotion Agency for R&amp;D Outcomes (COMPA)","award":["CRI18035-1"],"award-info":[{"award-number":["CRI18035-1"]}]},{"DOI":"10.13039\/501100002456","name":"Chonnam National University","doi-asserted-by":"publisher","award":["NRF-2020R1A2C1007473"],"award-info":[{"award-number":["NRF-2020R1A2C1007473"]}],"id":[{"id":"10.13039\/501100002456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002456","name":"Chonnam National University","doi-asserted-by":"publisher","award":["2022C100"],"award-info":[{"award-number":["2022C100"]}],"id":[{"id":"10.13039\/501100002456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002456","name":"Chonnam National University","doi-asserted-by":"publisher","award":["2019-0234"],"award-info":[{"award-number":["2019-0234"]}],"id":[{"id":"10.13039\/501100002456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002456","name":"Chonnam National University","doi-asserted-by":"publisher","award":["CRI18035-1"],"award-info":[{"award-number":["CRI18035-1"]}],"id":[{"id":"10.13039\/501100002456","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["NRF-2020R1A2C1007473"],"award-info":[{"award-number":["NRF-2020R1A2C1007473"]}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["2022C100"],"award-info":[{"award-number":["2022C100"]}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["2019-0234"],"award-info":[{"award-number":["2019-0234"]}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["CRI18035-1"],"award-info":[{"award-number":["CRI18035-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic or congenital hearing loss still has no definitive cure. Among genes related to genetic hearing loss, the potassium voltage-gated channel subfamily Q member 4 (KCNQ4) is known to play an essential role in maintaining ion homeostasis and regulating hair cell membrane potential. Variants of the KCNQ4 show reductions in the potassium channel activity and were responsible for non-syndromic progressive hearing loss. KCNQ4 has been known to possess a diverse variant. Among those variants, the KCNQ4 p.W276S variant produced greater hair cell loss related to an absence of potassium recycling. Valproic acid (VPA) is an important and commonly used histone deacetylase (HDAC) inhibitor for class I (HDAC1, 2, 3, and 8) and class IIa (HDAC4, 5, 7, and 9). In the current study, systemic injections of VPA attenuated hearing loss and protected the cochlear hair cells from cell death in the KCNQ4 p.W276S mouse model. VPA activated its known downstream target, the survival motor neuron gene, and increased acetylation of histone H4 in the cochlea, demonstrating that VPA treatment directly affects the cochlea. In addition, treatment with VPA increased the KCNQ4 binding with HSP90\u03b2 by inhibiting HDAC1 activation in HEI-OC1 in an in vitro study. VPA is a candidate drug for inhibiting late-onset progressive hereditary hearing loss from the KCNQ4 p.W276S variant.<\/jats:p>","DOI":"10.3390\/ijms24065695","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T03:33:57Z","timestamp":1679024037000},"page":"5695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1432-3321","authenticated-orcid":false,"given":"Yoon Seok","family":"Nam","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Mi","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0755-110X","authenticated-orcid":false,"given":"Sungsu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1331-4039","authenticated-orcid":false,"given":"Hyong-Ho","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/ajmg.1320460504","article-title":"Genetic epidemiological studies of early-onset deafness in the U.S. school-age population","volume":"46","author":"Marazita","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/cge.14228","article-title":"A systematic review of the monogenic causes of Non-Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options","volume":"103","author":"Sharma","year":"2023","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"C859","DOI":"10.1152\/ajpcell.2001.280.4.C859","article-title":"KCNQ4 channels expressed in mammalian cells: Functional characteristics and pharmacology","volume":"280","author":"Sogaard","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.1073\/pnas.97.8.4333","article-title":"KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway","volume":"97","author":"Kharkovets","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/416874a","article-title":"Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4","volume":"416","author":"Boettger","year":"2002","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/sj.emboj.7600951","article-title":"Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness","volume":"25","author":"Kharkovets","year":"2006","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16659","DOI":"10.1038\/s41598-018-34876-9","article-title":"Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss","volume":"8","author":"Jung","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/hmg\/8.7.1321","article-title":"Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families","volume":"8","author":"Coucke","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.7874\/kja.2013.17.2.45","article-title":"Pathophysiology of age-related hearing loss (peripheral and central)","volume":"17","author":"Lee","year":"2013","journal-title":"Korean J. Audiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.it.2011.04.001","article-title":"Histone deacetylases as regulators of inflammation and immunity","volume":"32","author":"Shakespear","year":"2011","journal-title":"Trends Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.joto.2017.04.002","article-title":"Histone deacetylases in hearing loss: Current perspectives for therapy","volume":"12","author":"Chen","year":"2017","journal-title":"J. Otol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.amjoto.2014.11.003","article-title":"Histone deacetylase inhibitor sodium butyrate attenuates gentamicin-induced hearing loss in vivo","volume":"36","author":"Wang","year":"2015","journal-title":"Am. J. Otolaryngol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1158\/0008-5472.CAN-03-0799","article-title":"Histone deacetylase is a target of valproic acid-mediated cellular differentiation","volume":"64","author":"Gurvich","year":"2004","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3904","DOI":"10.1172\/JCI79727","article-title":"M-current preservation contributes to anticonvulsant effects of valproic acid","volume":"125","author":"Kay","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e849","DOI":"10.1097\/MAO.0000000000003120","article-title":"Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study","volume":"42","author":"McLean","year":"2021","journal-title":"Otol. Neurotol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1172\/JCI29562","article-title":"Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy","volume":"117","author":"Avila","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1093\/hmg\/ddi130","article-title":"The role of histone acetylation in SMN gene expression","volume":"14","author":"Kernochan","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrd2133","article-title":"Anticancer activities of histone deacetylase inhibitors","volume":"5","author":"Bolden","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gao, Y., Yechikov, S., Vazquez, A.E., Chen, D., and Nie, L. (2013). Distinct roles of molecular chaperones HSP90alpha and HSP90beta in the biogenesis of KCNQ4 channels. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057282"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1874467210902010095","article-title":"Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection","volume":"2","author":"Monti","year":"2009","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1159\/000449467","article-title":"Roles of HDAC2 and HDAC8 in Cardiac Remodeling in Renovascular Hypertensive Rats and the Effects of Valproic Acid Sodium","volume":"99","author":"Li","year":"2017","journal-title":"Pharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/jbt.21807","article-title":"Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat","volume":"30","author":"Khan","year":"2016","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3892\/mmr.2015.4580","article-title":"Valproate attenuates diabetic nephropathy through inhibition of endoplasmic reticulum stress-induced apoptosis","volume":"13","author":"Sun","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112021","DOI":"10.1016\/j.biopha.2021.112021","article-title":"Hidden pharmacological activities of valproic acid: A new insight","volume":"142","author":"Singh","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1111\/j.1471-4159.2009.05871.x","article-title":"Aminoglycoside-induced histone deacetylation and hair cell death in the mouse cochlea","volume":"108","author":"Chen","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3892\/ijmm.2015.2236","article-title":"Association between histone deacetylases and the loss of cochlear hair cells: Role of the former in noise-induced hearing loss","volume":"36","author":"Wen","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1097\/01.mlg.0000197630.85208.36","article-title":"The histone deacetylase inhibitor sodium butyrate protects against cisplatin-induced hearing loss in guinea pigs","volume":"116","author":"Drottar","year":"2006","journal-title":"Laryngoscope"},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"832047","DOI":"10.3389\/fonc.2022.832047","article-title":"The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma","volume":"12","author":"Mazziotta","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells","volume":"20","author":"Gottlicher","year":"2001","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1093\/emboj\/cdg315","article-title":"The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2","volume":"22","author":"Kramer","year":"2003","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1111\/febs.15122","article-title":"Valproic acid targets HDAC1\/2 and HDAC1\/PTEN\/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer","volume":"287","author":"Sun","year":"2020","journal-title":"FEBS J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Forthun, R.B., Sengupta, T., Skjeldam, H.K., Lindvall, J.M., McCormack, E., Gjertsen, B.T., and Nilsen, H. (2012). Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048992"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s12668-016-0233-x","article-title":"Ubiquitin-Proteasome System: Promising Therapeutic Targets in Autoimmune and Neurodegenerative Diseases","volume":"6","author":"Bulatov","year":"2016","journal-title":"Bionanoscience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e139171","DOI":"10.1172\/jci.insight.139171","article-title":"Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration","volume":"6","author":"Wakizono","year":"2021","journal-title":"JCI Insight"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1212\/WNL.40.12.1896","article-title":"Sensorineural hearing loss: A reversible effect of valproic acid","volume":"40","author":"Armon","year":"1990","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.2169\/internalmedicine.42.1153","article-title":"Valproic acid-induced hearing loss and tinnitus","volume":"42","author":"Hori","year":"2003","journal-title":"Intern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/jcmm.12080","article-title":"Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss","volume":"17","author":"Gao","year":"2013","journal-title":"J. Cell. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.neuron.2012.05.019","article-title":"Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy","volume":"75","author":"Akil","year":"2012","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature25164","article-title":"Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents","volume":"553","author":"Gao","year":"2018","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.7150\/thno.67781","article-title":"In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model","volume":"12","author":"Noh","year":"2022","journal-title":"Theranostics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107931","DOI":"10.1016\/j.heares.2020.107931","article-title":"Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction","volume":"394","author":"Hastings","year":"2020","journal-title":"Hear. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5695\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:56:45Z","timestamp":1760122605000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,16]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065695"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065695","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,16]]}}}