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

초록

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.

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