Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer

// Mariko Kikuchi 1 , Keishi Yamashita 1,2 , Mina Waraya 1 , Naoko Minatani 1 , Hideki Ushiku 1 , Ken Kojo 1 , Akira Ema 1 , Yoshimasa Kosaka 1 , Hiroshi Katoh 1 , Norihiko Sengoku 1 , Takumo Enomoto 1 , Hirokazu Tanino 1 , Masakazu Sawanobori 2 and Masahiko Watanabe 1 1 Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan 2 Epigenetic Treatment Group, Japan Correspondence to: Masahiko Watanabe, email: // Keywords : phenylbutyrate, breast cancer, epigenetic, histone deacetylase (HDAC), ZEB1 Received : July 19, 2015 Accepted : November 15, 2015 Published : December 05, 2015 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.