title: Histone deacetylase inhibitors regulate P-gp expression in colorectal cancer via transcriptional activation and mRNA stabilization.
abstract: Histone deacetylase inhibitors (HDACIs) are emerging as a novel class of anti-tumor drugs. But the effect of HDACIs in tumors treatment has been disappointing, which mainly due to the acquisition of resistance to HDACIs. However, the underlying mechanisms have not been clearly understood. In this study, it was found that HDACIs SAHA and TSA increased P-gp expression in CRC cells, which has been well known to contribute to drug resistant. The mechanisms underlying these effects were investigated. We showed that HDACIs enhanced transcriptional activity of P-gp protein encoding gene ABCB1. HDACIs treatment also increased the protein and mRNA expression of STAT3, but not PXR, CAR, Foxo3a or β-catenin, which are known to be involved in ABCB transcription regulation. Interestingly, knockdown of STAT3 significantly attenuated HDACIs-induced P-gp up-regulation in colorectal cancer cells, suggesting that STAT3 plays a crucial role in HDACIs-up-regulated P-gp. Furthermore, this study revealed for the first time that HDACIs enhanced the stability of ABCB1 at post-transcriptional level. Taken together, these results proved that HDACIs induced P-gp expression by two distinct ways, transcriptional activation and mRNA stabilization. Our results suggested that more attention should be paid to the cancer treatment using HDACIs since they will induce multidrug resistance in cancer cells.
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Sichuan Cancer Hospital and Institute, Chengdu, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Anhui Provincial Cancer Hospital, West Branch of Anhui Provincial Hospital, Hefei, China.
authors.forename: Jing Mo
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Bing-Xiang
authors.initials: BX
authors.lastname: Zhan
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.
authors.forename: Bao-Long
authors.initials: BL
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C495270:CTNNB1 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin
keywords: P-gp; STAT3; histone deacetylase inhibitors; multidrug resistance; stability