RRC ID 63394
Author Kikuchi M, Yamashita K, Waraya M, Minatani N, Ushiku H, Kojo K, Ema A, Kosaka Y, Katoh H, Sengoku N, Enomoto T, Tanino H, Sawanobori M, Watanabe M.
Title Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer.
Journal Oncotarget
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.
Volume 7(2)
Pages 1741-53
Published 2016-1-12
DOI 10.18632/oncotarget.6480
PII 6480
PMID 26646320
PMC PMC4811494
MeSH Antineoplastic Agents / pharmacology Azacitidine / analogs & derivatives Azacitidine / pharmacology Breast Neoplasms / genetics Breast Neoplasms / metabolism Breast Neoplasms / pathology Cell Line, Tumor Decitabine Drug Resistance, Neoplasm / genetics Epigenesis, Genetic* Gene Expression Profiling / methods Gene Expression Regulation, Neoplastic / drug effects Humans Hydroxamic Acids / pharmacology Immunohistochemistry MCF-7 Cells Phenylbutyrates / pharmacology* RNA-Binding Proteins / genetics* RNA-Binding Proteins / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Signal Transduction / genetics Trastuzumab / pharmacology Zinc Finger E-box-Binding Homeobox 1 / genetics* Zinc Finger E-box-Binding Homeobox 1 / metabolism rab GTP-Binding Proteins / genetics* rab GTP-Binding Proteins / metabolism
IF 5.168
Human and Animal Cells MDA-MB-453(RCB1192) MCF7(RCB1904)