title: Role for Class I histone deacetylases in multidrug resistance.
abstract: Recent reports have showed that histone deacetylase (HDAC) inhibitor resulted in multidrug resistance (MDR) to other chemotherapeutic agents. However, the molecular mechanisms of Class I HDACs on MDR regulation are poorly understood. In this study, HDAC1 and HDAC2 acted as enhancers to intensify the chemosensitivities of anti-cancer drugs via reducing the expression levels of P-gp, MRP1 and MRP2. Furthermore, the dissociation of HDAC1 and HDAC2 led to transcriptional regulation of P-gp expression via the recruitment of p300, PCAF and NF-Y to the P-gp promoter region, which subsequently increased the level of the active gene marker, hyperacetylated histone H3. In parallel, selective inhibition of HDAC1 and HDAC2 induced the recruitment of p300, PCAF, NF-Y via acetylation of Sp1. Thus, our findings showed HDAC1 and 2 regulated P-gp expression through dynamic changes in chromatin structure and transcription factor association within the promoter region.
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Xu
authors.forename: Zijing
authors.initials: Z
authors.lastname: Jiang
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D000077337:Vorinostat
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D000077337:Vorinostat; D006655:Histone Deacetylases