{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:17:27Z","timestamp":1780568247454,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation","award":["2020R1A2C1006996"],"award-info":[{"award-number":["2020R1A2C1006996"]}]},{"name":"National Research Foundation","award":["2022R1F1A1060031"],"award-info":[{"award-number":["2022R1F1A1060031"]}]},{"name":"National Research Foundation","award":["2017M3A9G7072417"],"award-info":[{"award-number":["2017M3A9G7072417"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Histone deacetylase 9 (HDAC9) is known to be upregulated in various cancers. Cancer-associated antigens (CAGEs) are cancer\/testis antigens that play an important role in anti-cancer drug resistance. This study aimed to investigate the relationship between CAGEs and HDAC9 in relation to anti-cancer drug resistance. AGSR cells with an anti-cancer drug-resistant phenotype showed higher levels of CAGEs and HDAC9 than normal AGS cells. CAGEs regulated the expression of HDAC9 in AGS and AGSR cells. CAGEs directly regulated the expression of HDAC9. Rapamycin, an inducer of autophagy, increased HDAC9 expression in AGS, whereas chloroquine decreased HDAC9 expression in AGSR cells. The downregulation of HDAC9 decreased the autophagic flux, invasion, migration, and tumor spheroid formation potential in AGSR cells. The TargetScan analysis predicted that miR-512 was a negative regulator of HDAC9. An miR-512 mimic decreased expression levels of CAGEs and HDAC9. The miR-512 mimic also decreased the autophagic flux, invasion, migration, and tumor spheroid forming potential of AGSR cells. The culture medium of AGSR increased the expression of HDAC9 and autophagic flux in AGS. A human recombinant CAGE protein increased HDAC9 expression in AGS cells. AGSR cells displayed higher tumorigenic potential than AGS cells. Altogether, our results show that CAGE\u2013HDAC9\u2013miR-512 can regulate anti-cancer drug resistance, cellular proliferation, and autophagic flux. Our results can contribute to the understanding of the molecular roles of HDAC9 in anti-cancer drug resistance.<\/jats:p>","DOI":"10.3390\/cimb46060311","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T06:59:04Z","timestamp":1716533944000},"page":"5178-5193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HDAC9 and miR-512 Regulate CAGE-Promoted Anti-Cancer Drug Resistance and Cellular Proliferation"],"prefix":"10.3390","volume":"46","author":[{"given":"Minjeong","family":"Yeon","sequence":"first","affiliation":[{"name":"Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayeon","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewhoon","family":"Jeoung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dooil","family":"Jeoung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1006\/bbrc.2002.6701","article-title":"Identification and characterization of a novel cancer\/testis antigen gene CAGE","volume":"292","author":"Cho","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1158\/1078-0432.CCR-04-1702","article-title":"Frequent immune responses to a cancer\/testis antigen, CAGE, in patients with microsatellite instability-positive endometrial cancer","volume":"11","author":"Iwata","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1158\/1055-9965.EPI-17-0238","article-title":"The Prevalence of Cancer-Associated Autoantibodies in Patients with Gastric Cancer and Progressive Grades of Premalignant Lesions","volume":"26","author":"Meistere","year":"2017","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_4","first-page":"8","article-title":"A panel of cancer-testis genes exhibiting broad-spectrum expression in haematological malignancies","volume":"10","author":"Liggins","year":"2010","journal-title":"Cancer Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1196\/annals.1378.068","article-title":"DNA hypomethylation of CAGE promotors in squamous cell carcinoma of uterine cervix","volume":"1091","author":"Lee","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14475","DOI":"10.1074\/jbc.M109.084400","article-title":"The cancer\/testis antigen CAGE with oncogenic potential stimulates cell proliferation by up-regulating cyclins D1 and E in an AP-1- and E2F-dependent manner","volume":"285","author":"Por","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25957","DOI":"10.1074\/jbc.M109.095950","article-title":"Cancer\/testis antigen CAGE exerts negative regulation on p53 expression through HDAC2 and confers resistance to anti-cancer drugs","volume":"285","author":"Kim","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36502","DOI":"10.1074\/jbc.M113.502047","article-title":"miR-200b and cancer\/testis antigen CAGE form a feedback loop to regulate the invasion and tumorigenic and angiogenic responses of a cancer cell line to microtubule-targeting drugs","volume":"288","author":"Kim","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13632","DOI":"10.18632\/oncotarget.14621","article-title":"The pentapeptide Gly-Thr-Gly-Lys-Thr confers sensitivity to anti-cancer drugs by inhibition of CAGE binding to GSK3\u03b2 and decreasing the expression of cyclinD1","volume":"8","author":"Kim","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"54","DOI":"10.14348\/molcells.2017.2258","article-title":"DDX53 Promotes Cancer Stem Cell-Like Properties and Autophagy","volume":"40","author":"Kim","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yeon, M., Kim, Y., Pathak, D., Kwon, E., Kim, D.Y., Jeong, M.S., Jung, H.S., and Jeoung, D. (2021). The CAGE-MiR-181b-5p-S1PR1 Axis Regulates Anticancer Drug Resistance and Autophagy in Gastric Cancer Cells. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.666387"},{"key":"ref_12","first-page":"127","article-title":"Exosomes derived from Taxol-resistant nasopharyngeal carcinoma (NPC) cells transferred DDX53 to NPC cells and promoted cancer resistance to Taxol","volume":"25","author":"Yuan","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s13402-021-00626-9","article-title":"Histone deacetylase (HDAC) 9: Versatile biological functions and emerging roles in human cancer","volume":"44","author":"Yang","year":"2021","journal-title":"Cell. Oncol."},{"key":"ref_14","first-page":"11818","article-title":"Up-regulation of HDAC9 promotes cell proliferation through suppressing p53 transcription in osteosarcoma","volume":"8","author":"Zhao","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_15","first-page":"1483","article-title":"Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice","volume":"9","author":"Gil","year":"2016","journal-title":"Dis. Models Mech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0301-8","article-title":"Identification of HDAC9 as a viable therapeutic target for the treatment of gastric cancer","volume":"51","author":"Xiong","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3892\/ijmm.2021.4907","article-title":"Knockdown of long non-coding RNA HCP5 suppresses the malignant behavior of retinoblastoma by sponging miR-3619-5p to target HDAC9","volume":"47","author":"Zhu","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"544285","DOI":"10.3389\/fncel.2020.544285","article-title":"HDAC9 Silencing Exerts Neuroprotection Against Ischemic Brain Injury via miR-20a-Dependent Downregulation of NeuroD1","volume":"14","author":"Zhong","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"El-Awady, R., Saleh, E., Hamoudi, R., Ramadan, W.S., Mazitschek, R., Nael, M.A., Elokely, K.M., Abou-Gharbia, M., Childers, W.E., and Srinivasulu, V. (2021). Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents. Bioorg. Med. Chem., 42.","DOI":"10.1016\/j.bmc.2021.116251"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e131178","DOI":"10.1172\/JCI131178","article-title":"Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype","volume":"131","author":"Lecce","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/1120009X.2021.1963615","article-title":"Effect of HDAC9 inhibition on epithelial-mesenchymal transition in CD133+ prostate cancer cell lines","volume":"34","author":"Kim","year":"2022","journal-title":"J. Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41419-019-1763-2","article-title":"Increase in HDAC9 suppresses myoblast differentiation via epigenetic regulation of autophagy in hypoxia","volume":"10","author":"Zhang","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11092","DOI":"10.7150\/thno.44997","article-title":"Truncated HDAC9 identified by integrated genome-wide screen as the key modulator for paclitaxel resistance in triple-negative breast cancer","volume":"10","author":"Lian","year":"2020","journal-title":"Theranostics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.gpb.2020.09.003","article-title":"Phosphoproteomics Reveals AMPK Substrate Network in Response to DNA Damage and Histone Acetylation","volume":"20","author":"Jiang","year":"2021","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_25","first-page":"1403","article-title":"Long noncoding RNA CBR3 antisense RNA 1 promotes the aggressive phenotypes of non-small-cell lung cancer by sponging microRNA-509-3p and competitively upregulating HDAC9 expression","volume":"44","author":"Guan","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.21037\/tcr-20-3415","article-title":"PD-L1 combined with HDAC9 is a useful prognostic predictor in hepatocellular carcinoma","volume":"10","author":"Yang","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e26554","DOI":"10.1097\/MD.0000000000026554","article-title":"Expression and prognostic analyses of HDACs in human gastric cancer based on bioinformatic analysis","volume":"100","author":"Chen","year":"2021","journal-title":"Medicine"},{"key":"ref_28","first-page":"635","article-title":"MicroRNA-936 inhibits the malignant phenotype of retinoblastoma by directly targeting HDAC9 and deactivating the PI3K\/AKT pathway","volume":"43","author":"Xu","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kanki, K., Watanabe, R., Thai, L.N., Zhao, C.H., and Naito, K. (2020). HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth. Cancers, 12.","DOI":"10.3390\/cancers12102734"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/s41419-020-2708-5","article-title":"PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1\/2","volume":"11","author":"Huang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1007\/s11033-018-4389-z","article-title":"Expression profiles of histone modification genes in gastric cancer progression","volume":"45","author":"Kasap","year":"2018","journal-title":"Mol. Biol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejphar.2018.03.026","article-title":"A novel HDAC6 inhibitor exerts an anti-cancereffect by triggering cell cycle arrest and apoptosis in gastric cancer","volume":"828","author":"Dong","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jo, H., Shim, K., and Jeoung, D. (2022). Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179592"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41420-021-00771-y","article-title":"Circular RNA circRPPH1 promotes breast cancer progression via circRPPH1-miR-512-5p-STAT1 axis","volume":"7","author":"Huang","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1080\/21655979.2021.1882164","article-title":"Long non-coding RNA LINC00997 silencing inhibits the progression and metastasis of colorectal cancer by sponging miR-512-3p","volume":"12","author":"Shi","year":"2021","journal-title":"Bioengineered"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1089\/dna.2021.0059","article-title":"YY1-Induced lncRNA PART1 Enhanced Resistance of Ovarian Cancer Cells to Cisplatin by Regulating miR-512-3p\/CHRAC1 Axis","volume":"40","author":"Yang","year":"2021","journal-title":"DNA Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1038\/onc.2009.140","article-title":"Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells","volume":"28","author":"Saito","year":"2009","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"734694","DOI":"10.3389\/fonc.2021.734694","article-title":"SNHG8 Promotes the Progression of Epstein-Barr Virus-Associated Gastric Cancer via SpongingmiR-512-5p and Targeting TRIM28","volume":"11","author":"Zou","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9911","DOI":"10.18632\/aging.202747","article-title":"Exosomes derived from microRNA-512-5p-transfected bone mesenchymal stem cells inhibit glioblastoma progression by targeting JAG1","volume":"13","author":"Yan","year":"2021","journal-title":"Aging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e923817","DOI":"10.12659\/MSM.923817","article-title":"miR-512-3p Overcomes Resistance to Cisplatin in Retinoblastoma by Promoting Apoptosis Induced by Endoplasmic Reticulum Stress","volume":"26","author":"Kong","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113295","DOI":"10.1016\/j.jep.2020.113295","article-title":"Don extraction selectively targets stemness-prone NSCLC cells by attenuating SOX2\/SMO\/GLI1 network loop","volume":"265","author":"Chen","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"115071","DOI":"10.1016\/j.taap.2020.115071","article-title":"Eprinomectin, a novel semi-synthetic macrocylic lactone is cytotoxic to PC3 metastatic prostate cancer cells via inducing apoptosis","volume":"401","author":"Samy","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/s41388-021-02115-7","article-title":"Autophagy regulates the cancer stem cell phenotype of head and neck squamous cell carcinoma through the noncanonical FOXO3\/SOX2 axis","volume":"41","author":"Chen","year":"2022","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eaay6077","DOI":"10.1126\/scisignal.aay6077","article-title":"SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin","volume":"13","author":"Bhattacharya","year":"2020","journal-title":"Sci. Signal"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e001037","DOI":"10.1136\/jitc-2020-001037","article-title":"SOX2 promotes resistance of melanoma with PD-L1 high expression to T-cell-mediated cytotoxicity that can be reversed by SAHA","volume":"8","author":"Wu","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.biopha.2017.09.129","article-title":"Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune","volume":"96","author":"Jiang","year":"2017","journal-title":"Biomed. Pharmacother."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/6\/311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:48:02Z","timestamp":1760107682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/6\/311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,24]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["cimb46060311"],"URL":"https:\/\/doi.org\/10.3390\/cimb46060311","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,24]]}}}