title: Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer.
abstract: Phenylbutyrate (PB) is a histone deacetylase antagonist that also exhibits antitumor activity. In this study, we used 7 breast cancer cell lines to identify biomarker candidates that predict PB sensitivity in breast cancer.Comprehensive gene expression profiles were compared using microarrays, and the importance of the identified genes to PB sensitivity was confirmed in gene transfection experiments. CRL and MDAMB453 cells were identified as PB-sensitive, while MDAMB231 cells were PB-resistant.RAB25 and ESRP1 were identified as key regulators of PB sensitivity, while ANKD1, ETS1, PTRF, IFI16 and KIAA1199 acted as PB resistance-related genes. Expression of these genes was dramatically altered by DNA demethylation treatments. RAB25 expression inhibited IFI16 and PTRF, while ESRP1 expression suppressed ANKRD1, ETS1, and KIAA1199. Both RAB25 and ESRP1 were suppressed by ZEB1, which was in turn regulated via epigenetic mechanisms. Thus, PB sensitivity is influenced by epigenetic expression alteration of ZEB1. The genes associated with PB sensitivity are downstream targets of ZEB1. Epigenetic regulation of ZEB1 may prove valuable as a critical biomarker for predicting resistance to breast cancer therapies.
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.|Epigenetic Treatment Research Group, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Waraya
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Minatani
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ushiku
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kojo
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ema
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kosaka
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katoh
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sengoku
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Takumo
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanino
authors.affiliation: Epigenetic Treatment Research Group, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sawanobori
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D010654:Phenylbutyrates / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000068878:Trastuzumab / Q000494:pharmacology; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics* / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C539364:ESRP1 protein, human; D006877:Hydroxamic Acids; D010654:Phenylbutyrates; D016601:RNA-Binding Proteins; C509763:Rab25 protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C012589:trichostatin A; D000077209:Decitabine; D020691:rab GTP-Binding Proteins; D001374:Azacitidine; D000068878:Trastuzumab
keywords: ZEB1; breast cancer; epigenetic; histone deacetylase (HDAC); phenylbutyrate