Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs

• Published in: Molecules and cells 2015, 38(8), , pp.705-714
• Main Authors: Kim, Y., Kangwon National University, Chunchon, Republic of Korea, Kim, H., Kangwon National University, Chunchon, Republic of Korea, Jeoung, D., Kangwon National University, Chunchon, Republic of Korea
• Format: Article
• Language: English
• Subjects: anti-cancer drug-resistance,expression regulation,HDAC3,tubulin beta 3; Antineoplastic Agents - metabolism; ATP Binding Cassette Transporter, Subfamily B - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm; DRUGS; Gene Expression - drug effects; Histone Deacetylase 6; Histone Deacetylases - metabolism; Humans; MEDICAMENT; MEDICAMENTOS; Microtubules - metabolism; Paclitaxel - pharmacology; Pentacyclic Triterpenes; Promoter Regions, Genetic; Triterpenes - pharmacology; Tubulin - metabolism; 생물학
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2015.0086

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 beta 3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin beta 3 and HDAC6. HDAC6 showed an interaction with tubulin beta 3. HDAC3 had a negative regulatory role in the expression of tubulin beta 3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin beta 3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin beta 3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin beta 3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin beta 3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin beta axis can be employed for the development of anti-cancer drugs.