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1. Cancer Res. 2012 Apr 3. [Epub ahead of print]

Histone deacetylase inhibitors influence chemotherapy transport by modulating
expression and trafficking of a common polymorphic variant of the ABCG2 efflux
transporter.

Basseville A, Tamaki A, IeranĂ² C, Trostel S, Ward Y, Robey RW, Hegde RS, Bates
SE.

National Cancer Institute, National Institutes of Health.

Histone deacetylase inhibitors (HDIs) 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. Inscreening for compounds that could correct its
expression, localization and function, we found that the microtubule disrupting
agent colchicine could induce re-localization of the variant from the aggresome
to the cell surface. More strinkingly, we found that HDIs could produce a
similareffect 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 butinstead 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.

PMID: 22472121 [PubMed - as supplied by publisher]