Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

Abstract

Abstract. Enhancer of zeste homolog 2 (EZH2) is involved in malignant transformation and the biological aggressiveness of several human malignancies. Growing evidence indicates that EZH2 may be an appropriate therapeutic target for malignancies, including cholangiocarcinoma. Recently, an S-adenosyl-L-homocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep) was shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep and the combination of gemcitabine and DZNep in cholangiocarcinoma cells. The effects of DZNep and its combination with gemcitabine were assessed in the cholangiocarcinoma cell lines RBE and TFK-1. DZNep depleted the cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. DZNep treatment resulted in the inhibition of proliferation in the cholangiocarcinoma cell lines, and the combination of DZNep and gemcitabine showed synergistic inhibition of cell proliferation. DZNep induced apoptosis and G1 phase cell cycle arrest in cholangiocarcinoma cells, and the combination of DZNep and gemcitabine enhanced the induced apoptosis and G1 arrest when compared with gemcitabine alone. Inhibition of cell proliferation by DZNep was partially associated with upregulation of p16INK4a and p17 KIP1. The present study shows that DZNep inhibits cell proliferation by inducing G1 arrest and apoptosis. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach for the treatment of cholangiocarcinoma.

The KDM2B- Let-7b -EZH2 Axis in Myelodysplastic Syndromes as a Target for Combined Epigenetic Therapy

“…EZH2 expression in primary MDS cells is maintained by the histone demethylase KDM2B. Results presented here, as well as previous reports [16], [33], [34] indicate that depletion of EZH2, be it by genetic inhibition or by the use of DZNep, interferes with cell-cycle progression through S and G2/M phases and with survival of clonogenic cells by allowing for increased apoptosis. Combined exposure to DZNep and 5AZA resulted in enhanced cytotoxicity against MDS cells, providing a rationale to develop and test this drug combination in patients with MDS.…”

BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma

“…We observed an increase in EZH2 protein and reduced SETD8 with siRNA knockdown of BAP1 confirming that EZH2 represents a potential therapeutic target that could be modulated by BAP1. Combination therapy of an EZH2 inhibitor, 3-deazaneplanocin A, and gemcitabine has had potent synergistic effects in CCA cells by causing cell cycle arrest and increased apoptosis [36]. …”

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…Indeed, EZH2 is typically overexpressed in cholangiocarcinomas, and EZH2 upregulation is correlated with a poor prognosis 131,132 . Furthermore, preclinical data indicate that EZH2 inhibition, in combination with gemcitabine, synergistically inhibits cholangiocarcinoma- cell proliferation 133 . Several active clinical trials are investigating EZH2 inhibitors, such as tazemetostat, but primarily in patients with haematopoietic or rhabdoid tumours.…”