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.

Carcinosarcoma of the esophagus: A report of 6 cases associated with zinc finger E‑box‑binding homeobox 1 expression

“…For the treatment of recurrent tumors with expected anticancer drug resistance, no further promising results will be obtained unless molecular targeted treatment is applied. In addition, in a previous study in our laboratory (Department of Surgery, Kitasato University School of Medicine), it was confirmed that the suppression of ZEB1 expression in triple-negative breast cancer resulted in a loss of resistance to phenylbutyrate in the majority of cases (13). Based on the aforementioned finding, the present study aimed to indicate the molecular uniqueness of ESC by confirming its specificity, as numerous molecules could be associated with EMT, including ZEB1, Snail 1 and Twist 1.…”

“…As a control tissue of ZEB1 in the present study, according to the study by Kikuchi et al (13), mammary gland tissues were also stained. Triple-negative breast cancer tissues demonstrating the strongest staining were used as a positive control, whereas normal breast tissues that did exhibit staining were used as a negative control (13). The positive and negative controls were primary tumors and the corresponding non-cancerous tissues from 3 patients with triple-negative invasive breast cancer who all underwent a partial resection of the breast in September 1999 at Kitasato University Hospital.…”

Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target

“…ESRP1 was an independent indicator for EMT process, the negative regulation of it was maintained by ZEB1 expression, while ESRP1 was upstream suppressor for CEMIP. Besides, both ESRP1 and ZEB1 was involved in FGFR signaling pathway which suggested CEMIP could be a cross-linker in this pathway 39 .…”

ASO Author Reflections: ASCL2, a Marker of Dynamic Colon Stem Cell, Involved in Wnt Pathway Activation Reflects Anti-cancer Drug Resistance in Primary Colorectal Cancer

“…We applied a phenylbutyrate administration model, previously used for exploration of genes involved in drug resistance in breast cancer and searched novel genes explaining drug resistance to CRC. 1 In the current study, ASCL2 was significantly associated with resistance against phenylbutyrate, 5-FU, and radiotherapy. 2 The regulation of ASCL2 may provide a clue for the molecular understanding of CRC treatment failure.…”