title: Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs.
abstract: We investigated the role of HDAC3 in anti-cancer drug-resistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The down-regulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin β3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin β3 and HDAC6. HDAC6 showed an interaction with tubulin β3. HDAC3 had a negative regulatory role in the expression of tubulin β3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin β3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin β3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin β3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin β3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin β axis can be employed for the development of anti-cancer drugs.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Hyuna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression / Q000187:drug effects; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D011401:Promoter Regions, Genetic; D014315:Triterpenes / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014404:Tubulin; D000099186:Histone Deacetylase 3; C513055:ABCB1 protein, human; C433811:HDAC6 protein, human; C050414:celastrol
keywords: HDAC3; anti-cancer drug-resistance; expression regulation; tubulin beta 3