Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter.
Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter.
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DOI：
10.1158/0008-5472.can-11-2008
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Bates SE
中科院分区：
文献类型：
--
作者：
Basseville A;Tamaki A;Ierano C;Trostel S;Ward Y;Robey RW;Hegde RS;Bates SE
组蛋白去乙酰化酶抑制剂（HDI）在临床试验中表现出一定的疗效，但很明显，它们最有效的应用尚未完全确定。在这项研究中，我们发现HDIs影响化疗药物外排转运蛋白ABCG 2的一种常见多态性变体的表达，这有助于正常组织的保护。作为人类ABCG2中最常见的变体之一，多态性Q141K损害表达、定位和功能，从而降低药物清除率并增加化疗毒性。机制研究表明，ABCG2 Q141K变体被完全加工，但保留在侵略组中，这是一种核周结构，错误折叠的蛋白质聚集在此。在筛选可以纠正其表达、定位和功能的化合物时，我们发现微管破坏剂秋水仙碱可以诱导该变体从侵袭基因组重新定位到细胞表面。更引人注目的是，我们发现HDIs可以产生类似的效果，但也可以将蛋白质表达恢复到野生型水平，从而恢复ABCG 2介导的特异性药物外排活性。值得注意的是，HDIs并没有改变侵略组结构，而是拯救了新合成的蛋白质并阻止侵略组靶向，这表明HDIs通过引起马达蛋白表达的变化来扰乱沿着微管的运输。总之，这些结果显示了HDIs如何能够恢复ABCG 2的常见Q141K多态性同种型的野生型功能。更广泛地说，我们的研究结果扩大了HDI在临床中的潜在用途。
Histone deacetylase inhibitors (HDI) have exhibited some efficacy in clinical trials, but it is clear that their most effective applications have yet to be fully determined. In this study, we show that HDIs influence the expression of a common polymorphic variant of the chemotherapy drug efflux transporter ABCG2, which contributes to normal tissue protection. As one of the most frequent variants in human ABCG2, the polymorphism Q141K impairs expression, localization, and function, thereby reducing drug clearance and increasing chemotherapy toxicity. Mechanistic investigations revealed that the ABCG2 Q141K variant was fully processed but retained in the aggresome, a perinuclear structure, where misfolded proteins aggregate. In screening for compounds that could correct its expression, localization, and function, we found that the microtubule-disrupting agent colchicine could induce relocalization of the variant from the aggresome to the cell surface. More strikingly, we found that HDIs could produce a similar effect but also restore protein expression to wild-type levels, yielding a restoration of ABCG2-mediated specific drug efflux activity. Notably, HDIs did not modify aggresome structures but instead rescued newly synthesized protein and prevented aggresome targeting, suggesting that HDIs disturbed trafficking along microtubules by eliciting changes in motor protein expression. Together, these results showed how HDIs are able to restore wild-type functions of the common Q141K polymorphic isoform of ABCG2. More broadly, our findings expand the potential uses of HDIs in the clinic.