Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs.
Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs.
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DOI：
10.14348/molcells.2015.0086
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发表时间：
2015-08
影响因子：
3.8
通讯作者：
Jeoung D
中科院分区：
文献类型：
--
作者：
Kim Y;Kim H;Jeoung D
我们研究了HDAC3在抗癌耐药中的作用。在抗癌药物如celastrol和taxol耐药的癌细胞系中，HDAC3的表达降低。HDAC3对这些抗癌药物具有敏感性。HDAC3活性对于赋予这些抗癌药物敏感性是必要的。HDAC3的下调增加了MDR1的表达，使其对抗癌药物产生耐药性。耐药癌细胞中微管蛋白β3表达升高。ChIP实验显示HDAC3与微管蛋白β3和HDAC6的启动子序列结合。HDAC6与微管蛋白β3相互作用。HDAC3对微管蛋白β3和HDAC6的表达有负调控作用。HDAC6的下调降低了MDR1和微管蛋白β3的表达，但不影响HDAC3的表达。HDAC6的下调使其对紫杉醇敏感。微管蛋白β3的下调不影响HDAC6和MDR1的表达。微管蛋白β3的下调使其对抗癌药物具有敏感性。我们的研究结果表明，微管蛋白β3作为HDAC3的下游靶点，介导对微管靶向药物的耐药性。因此，HDAC3-HDAC6-Tubulin β轴可用于抗癌药物的开发。
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.