Abstract
Histone deacetylases (HDACs) have been implicated in multiple malignant tumors, and HDAC inhibitors (HDACIs) exert anti-cancer effects. However, the expression of HDACs and the anti-tumor mechanism of HDACIs in cholangiocarcinoma (CCA) have not yet been elucidated. In this study, we found that expression of HDACs 2, 3, and 8 were up-regulated in CCA tissues and those patients with high expression of HDAC2 and/or HDAC3 had a worse prognosis. In CCA cells, two HDACIs, trichostatin (TSA) and vorinostat (SAHA), suppressed proliferation and induced apoptosis and G2/M cycle arrest. Microarray analysis revealed that TACC3 mRNA was down-regulated in CCA cells treated with TSA. TACC3 was highly expressed in CCA tissues and predicted a poor prognosis in CCA patients. TACC3 knockdown induced G2/M cycle arrest and suppressed the invasion, metastasis, and proliferation of CCA cells, both in vitro and in vivo. TACC3 overexpression reversed the effects of its knockdown. These findings suggest TACC3 may be a useful prognostic biomarker for CCA and is a potential therapeutic target for HDACIs.
Highlights
Cholangiocarcinoma (CCA) originates from the epithelial cells of the intra- and extra-hepatic biliary trees and is the second most common hepatobiliary malignancy after hepatocellular carcinoma [1]
Histone deacetylases (HDACs) protein expression was assayed by Western blot (WB), and the expression of HDAC2, HDAC3, and HDAC8 were higher in CCA tissues compared with paired non-tumor tissues (P
Kaplan-Meier analysis showed that patients with low expression of HDAC2 and/or HDAC3 exhibited a longer overall survival (OS) than those with high expression of HDAC2 and/or HDAC3 (P
Summary
Cholangiocarcinoma (CCA) originates from the epithelial cells of the intra- and extra-hepatic biliary trees and is the second most common hepatobiliary malignancy after hepatocellular carcinoma [1]. Morbidity due to CCA has been rising worldwide over the past several decades [2]. Due to the strong and early invasive characteristics of CCA, most patients are diagnosed in the later stages of disease. More than two-thirds of patients are ineligible for surgery, the only potential curative option. Most CCA patients resort to palliative treatments, such as chemotherapy and radiotherapy, with a response of only 10-20% [3,4,5].
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