6月25日，Cancer Research 在線報道,，組蛋白去乙酰酶抑制劑（HDI）可影響化療藥物細胞膜轉運蛋白ABCG2的多態(tài)性變體的表達和轉運。這拓展了HDI的臨床應用空間,。
組蛋白去乙酰酶抑制劑（HDI）在臨床試驗中已經表現(xiàn)出一定的療效,，但很顯然，它們最有效的應用價值尚未完全開發(fā)出來,。
這項研究表明,，HDI可影響化療藥物外排轉運蛋白ABCG2的表達。ABCG2可為正常組織提供保護,。作為人類ABCG2最常見的一種變體,，Q141K突變可損害ABCG2的表達，定位,，功能,，從而減少藥物清除，并增加化療毒性,。
研究顯示,，ABCG2的Q141K突變體被完全處理，但駐留在核周結構--聚集體中,。這正是錯誤折疊的蛋白質聚集的場所,。在篩選可以糾正ABCG2突變體的表達，定位和功能異常的治療性化合物時,，研究者發(fā)現(xiàn),，微管干擾劑秋水仙堿可誘導ABCG2的Q141K突變體從聚集體重新定位到細胞表面上。更引人注目的是,，研究者還發(fā)現(xiàn),，HDI可產生類似的效果,，并且還使蛋白表達恢復到野生型的水平，可恢復ABCG2介導特定藥物外排的活力,。
值得注意的是,，HDI沒有修飾聚集體的結構，而是解救新合成的蛋白質,，阻止聚集體靶向ABCG2蛋白,。這提示，HDI通過引發(fā)馬達蛋白的改變干擾沿微管結構的運輸過程,。
總之,，這些結果表明，HDI是如何恢復ABCG2蛋白Q141K突變體的野生型功能的,。更廣泛的,，該研究結果擴大HDI在臨床上的潛在用途。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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PMID:
Histone Deacetylase Inhibitors Influence Chemotherapy Transport by Modulating Expression and Trafficking of a Common Polymorphic Variant of the ABCG2 Efflux Transporter
Agnes Basseville1, Akina Tamaki1, Caterina Ierano1, Shana Trostel1, Yvona Ward2, Robert W. Robey1, Ramanujan S. Hegde3, and Susan E. Bates1
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.
