title: Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter.
abstract: 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.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Basseville
authors.forename: Akina
authors.initials: A
authors.lastname: Tamaki
authors.forename: Caterina
authors.initials: C
authors.lastname: Ierano
authors.forename: Shana
authors.initials: S
authors.lastname: Trostel
authors.forename: Yvona
authors.initials: Y
authors.lastname: Ward
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D008942:Mitoxantrone