{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:19:34Z","timestamp":1791983974582,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Adenoid Cystic Carcinoma Research Foundation (ACCRF)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms25031646","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T08:11:27Z","timestamp":1706515887000},"page":"1646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel Epigenetic Modifiers of Histones Presenting Potent Inhibitory Effects on Adenoid Cystic Carcinoma Stemness and Invasive Properties"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8205-9935","authenticated-orcid":false,"given":"Paulo S. S.","family":"Pina","sequence":"first","affiliation":[{"name":"Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Stomatology, School of Dentistry, University of S\u00e3o Paulo, Sao Paulo 05508-270, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeejin","family":"Jang","sequence":"additional","affiliation":[{"name":"Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6904-3242","authenticated-orcid":false,"given":"Carolina","family":"Emerick","sequence":"additional","affiliation":[{"name":"Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Oral Diagnosis Department, Piracicaba School of Dentistry, State University of Campinas, Piracicaba 13414-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9015-6831","authenticated-orcid":false,"given":"Jo\u00e3o Figueira","family":"Scarini","sequence":"additional","affiliation":[{"name":"Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Oral Diagnosis Department, Piracicaba School of Dentistry, State University of Campinas, Piracicaba 13414-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana C. 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Pathol. Lab. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/hed.23925","article-title":"Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials","volume":"38","author":"Dillon","year":"2016","journal-title":"Head Neck"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.scr.2017.04.003","article-title":"Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence","volume":"21","author":"Almeida","year":"2017","journal-title":"Stem. Cell Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"206","DOI":"10.14639\/0392-100X-N1379","article-title":"Adenoid cystic carcinoma. An indolent but aggressive tumour. Part A: From aetiopathogenesis to diagnosis","volume":"41","author":"Cantu","year":"2021","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.14639\/0392-100X-N1729","article-title":"Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: Treatment and prognosis","volume":"41","author":"Cantu","year":"2021","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_6","unstructured":"Silva, L.C., Perez-de-Oliveira, M.E., Pedroso, C.M., Leite, A.A., Santos-Silva, A.R., Lopes, M.A., Junior, G.D., Martins, M.D., Wagner, V.P., and Kowalski, L.P. (2023). Systemic therapies for salivary gland carcinomas: An overview of published clinical trials. Med. Oral Patol. Oral Cir. Bucal., 26264. online ahead of print."},{"key":"ref_7","first-page":"880","article-title":"Chemotherapy targeting cancer stem cells","volume":"5","author":"Liu","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"769","DOI":"10.47162\/RJME.61.3.15","article-title":"The immunophenotype of epithelial to mesenchymal transition inducing transcription factors in salivary gland adenoid cystic carcinomas","volume":"61","author":"Belulescu","year":"2020","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2217\/fon.12.19","article-title":"High-throughput screening strategies for targeted identification of therapeutic compounds in colorectal cancer","volume":"8","author":"Bialkowska","year":"2012","journal-title":"Future Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.radonc.2020.03.047","article-title":"Dihydroouabain, a novel radiosensitizer for cervical cancer identified by automated high-throughput screening","volume":"148","author":"Li","year":"2020","journal-title":"Radiother. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Henikoff, S., and Smith, M.M. (2015). Histone variants and epigenetics. Cold Spring Harb. Perspect. Biol., 7.","DOI":"10.1101\/cshperspect.a019364"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1586\/14789450.2.5.719","article-title":"Histone structure and nucleosome stability","volume":"2","author":"Kann","year":"2005","journal-title":"Expert Rev. Proteom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/iju.14406","article-title":"Epigenetic modifications in prostate cancer","volume":"28","author":"Sugiura","year":"2021","journal-title":"Int. J. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1177\/1947601911417176","article-title":"Histone modifiers in cancer: Friends or foes?","volume":"2","author":"Cohen","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2010.08.011","article-title":"The language of histone crosstalk","volume":"142","author":"Lee","year":"2010","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.cell.2014.09.037","article-title":"SnapShot: Histone modifications","volume":"159","author":"Huang","year":"2014","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.tripleo.2010.06.015","article-title":"Correlation between transcription factor Snail1 expression and prognosis in adenoid cystic carcinoma of salivary gland","volume":"110","author":"Jiang","year":"2010","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2009.11.007","article-title":"Epithelial-mesenchymal transitions in development and disease","volume":"139","author":"Thiery","year":"2009","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1146\/annurev-cellbio-092910-154036","article-title":"The ins and outs of the epithelial to mesenchymal transition in health and disease","volume":"27","author":"Nieto","year":"2011","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Audia, J.E., and Campbell, R.M. (2016). Histone Modifications and Cancer. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a019521"},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc1779","article-title":"Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer","volume":"6","author":"Minucci","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","first-page":"143","article-title":"Using PDX animal models to identify and stratify adenoid cystic carcinoma patients presenting an enhanced response to HDAC inhibitors","volume":"13","author":"Guimaraes","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"106437","DOI":"10.1016\/j.oraloncology.2023.106437","article-title":"Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma","volume":"142","author":"Sahara","year":"2023","journal-title":"Oral Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/hed.21315","article-title":"Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase","volume":"32","author":"Clay","year":"2010","journal-title":"Head Neck"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2174\/15680096113136660102","article-title":"The Role of Snail in EMT and Tumorigenesis","volume":"13","author":"Wang","year":"2013","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.yexmp.2010.05.008","article-title":"SNAIL induces epithelial-to-mesenchymal transition in a human pancreatic cancer cell line (BxPC3) and promotes distant metastasis and invasiveness in vivo","volume":"89","author":"Nishioka","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer","volume":"20","author":"Dongre","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/ncb1173","article-title":"Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition","volume":"6","author":"Zhou","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/COC.0b013e3181d26d45","article-title":"Determinants and patterns of survival in adenoid cystic carcinoma of the head and neck, including an analysis of adjuvant radiation therapy","volume":"34","author":"Lloyd","year":"2011","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.oraloncology.2018.10.012","article-title":"UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line","volume":"87","author":"Warner","year":"2018","journal-title":"Oral Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27424","DOI":"10.1074\/jbc.M100827200","article-title":"A new role for E12\/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions","volume":"276","author":"Locascio","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1387\/ijdb.041794hp","article-title":"Transcriptional regulation of cadherins during development and carcinogenesis","volume":"48","author":"Peinado","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/35000025","article-title":"The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression","volume":"2","author":"Cano","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101016","DOI":"10.1016\/j.drup.2023.101016","article-title":"Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance","volume":"72","author":"Zhu","year":"2024","journal-title":"Drug Resist. Updat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/jop.13252","article-title":"Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells","volume":"51","author":"Silva","year":"2022","journal-title":"J. Oral Pathol. Med."},{"key":"ref_39","first-page":"6038","article-title":"Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFkappaB and histone deacetylation inhibition","volume":"13","author":"Silva","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1158\/1535-7163.MCT-13-0963","article-title":"Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: A novel potential strategy in acute myelogenous leukemia","volume":"13","author":"Guzman","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.oraloncology.2015.06.004","article-title":"BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma","volume":"51","author":"Acasigua","year":"2015","journal-title":"Oral Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s13402-018-0416-2","article-title":"Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma","volume":"42","author":"Markman","year":"2019","journal-title":"Cell Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Martins, M.D., Silveira, F.M., Webber, L.P., Wagner, V.P., Martins, M.A.T., Squarize, C.H., and Castilho, R.M. (2020). The impact of photobiomodulation therapy on the biology and behavior of head and neck squamous cell carcinomas cell lines. J. Photochem. Photobiol. B, 209.","DOI":"10.1016\/j.jphotobiol.2020.111924"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Chen, I.P. (2020). Differentiation of Human Induced Pluripotent Stem Cells (hiPSCs) into Osteoclasts. Bio Protoc., 10.","DOI":"10.21769\/BioProtoc.3854"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Johnson, S., Chen, H., and Lo, P.K. (2013). In vitro Tumorsphere Formation Assays. Bio Protoc., 3.","DOI":"10.21769\/BioProtoc.325"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Almeida, L.O., Guimaraes, D.M., Squarize, C.H., and Castilho, R.M. (2016). Profiling the Behavior of Distinct Populations of Head and Neck Cancer Stem Cells. Cancers, 8.","DOI":"10.3390\/cancers8010007"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1646\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:51:06Z","timestamp":1760104266000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25031646"],"URL":"https:\/\/doi.org\/10.3390\/ijms25031646","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,29]]}}}