Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Abstract

Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells

“…Since metabolic reprogramming in tumor cells could possibly endow the cells with resistance to chemotherapies (30,31), we thought that low concentrations of metformin could alter the metabolic abnormalities of tumor cells, causing the cells to become fragile and sensitive to chemotherapy. Our previous data showed that HDAC3 is a potential chemotherapeutic target (20). However, the present study found that the new selective HDAC3 inhibitor, BG45, could hardly induce CCA cellular apoptosis.…”

“…HuCCT1 and RBE cells were transfected using Lipofectamine RNAiMax reagent (Invitrogen; Thermo Fisher Scientific, Inc.), following the manufacturer's protocol. HDAC3 siRNA was produced as described previously (20). Briefly, 50 pmol siRNA and 0.5 ml Opti-MEM I Medium (Invitrogen; Thermo Fisher Scientific, Inc.) were mixed, and then 5.5 µl RNAiMax reagent was added to each well of a 6-well plate and incubated for 15 min.…”

“…Recent studies suggest that Class-I HDACs are upregulated in many malignancies, and that they inhibit the expression of specific tumor-suppressor genes through epigenetic modulation (17)(18)(19). Our previous studies demonstrated that high levels of HDAC3 expression and activity play a critical role in CCA, and that the inhibition of HDAC3 could induce apoptosis in CCA cells (20).…”

“…It is possible that reversing the Warburg effect in CCA cells with metformin could then increase tumor cell fragility and render them more susceptible to chemotherapy (14,28). Recently, we found that HDAC3 inhibitors are promising chemotherapeutic agents in the treatment of CCA (20). BG45, a novel HDAC3 selective inhibitor, has been validated as a therapeutic agent in multiple myeloma (16).…”

The Plasma LncRNA Acting as Fingerprint in Hilar Cholangiocarcinoma

“…Despite recent improvements in cholangiocarcinoma treatment, surgical resection and transplantation is still the main therapy, as this can cure early-staged patients [5,6]. Unfortunately, there are no specific biomarkers or unique clinical manifestations for cholangiocarcinoma, meanwhile, HC is typically characterized by advanced stage diagnosis.…”