title: Upregulation of ABCG2 by romidepsin via the aryl hydrocarbon receptor pathway.
abstract: Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line-specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Hong Kong. kennethto@cuhk.edu.hk
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.forename: Robert
authors.initials: R
authors.lastname: Robey
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhan
authors.forename: Lois
authors.initials: L
authors.lastname: Bangiolo
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 / Q000096:biosynthesis* / Q000235:genetics; D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements; D015854:Up-Regulation / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; C497396:ARNT protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C087123:romidepsin