SAHA Down-Regulates the Expression of Indoleamine 2,3-Dioxygenase Via Inhibition of the JAK/STAT1 Signaling Pathway in Gallbladder Carcinoma Cells

The aim of the present study was to investigate the role of the JAK/STAT1 signaling pathway in suberoylanilide hydroxamic acid (SAHA)-mediated down-regulation of indoleamine 2,3-dioxygenase (IDO) in gallbladder carcinoma cells. We treated SGC-996 gallbladder carcinoma cells with IFN-gamma and SAHA. Western blotting was used to detect the expression of IDO. signal transducer and activator of transcription 1 (STAT1) phosphorylation and interferon regulatory factor genes-1 (IRF-1). Confocal microscopy analysis was used to detect STAT1 translocation. Transient transfection and reporter gene assay was used for detecting the activation of gamma-activated sites (GAS) and interferon-stimulated response elements (ISRE). The results revealed that IDO was expressed in SGC-996 cells in a dose- and time-dependent manner when stimulated with IFN-gamma and SAHA down-regulated the expression of IDO induced by IFN-gamma in a dose-dependent manner. SAHA blocked the expression of IRF-1 induced by IFN-gamma and SAHA inhibited IFN-gamma-induced STAT1 phosphorylation and nuclear translocation. In addition, SAHA down-regulated IFN-gamma-induced activation of GAS and ISRE. In conclusion, SAHA down-regulated IDO expression via inhibition of the activation of members of the JAK/STAT1 signaling pathway. Therefore, regulation of the JAK/STAT1 signaling pathway may provide a new gallbladder carcinoma immunotherapeutic strategy to break tumor immune tolerance.