Chidamide and decitabine can synergistically induce apoptosis of Hodgkin lymphoma cells by up-regulating the expression of PU.1 and KLF4.

Tao Jiang,Yongqian Jia,Fujue Wang,Xiaomin Cheng,Lianjie Hu,Yuhuan Zheng,Ting Liu

doi:10.18632/oncotarget.20659

Abstract

Epigenetic abnormalities play important roles in the pathogenesis of Hodgkin lymphoma (HL). Highly expressed class I histone acetyltransferase (HDAC) and hyper-methylation of the promoter region of tumor suppressor genes have been demonstrated in Hodgkin lymphoma. In this paper, we investigated the synergistic effects of combination treatment of chidamide, a selective HDAC inhibitor, and decitabine, a demethylation agent, for HL cell lines and explored a new strategy for treating HL. The apoptosis rates, cell cycle, mitochondrial transmembrane potentials, epigenetic changes and gene expression of HL cell lines treated with chidamide as a single agent and in combination with decitabine were tested. We found that chidamide inhibited the proliferation of HL cells through increased apoptosis. Interestingly, after combined with decitabine, the inhibition rate and apoptotic death in HL cells were significantly increased. Further studies demonstrated that when combined with decitabine the expression of acetylated histone H3 and H3K9 induced by chidamide in HL cells increased, and also the expression of tumor suppressor genes PU.1 and KLF4, which exert inhibition through apoptosis pathway. Therefore, we could come to a conclusion that chidamide and decitabine can synergistically induce apoptosis of Hodgkin lymphoma cells by up-regulating the expression of PU.1 and KLF4. These results provide a new sight in combining two different epigenetic regulatory agents for treating HL.

Highlights

Hodgkin lymphoma (HL) is a well-established malignancy and accounts for about 8~13% of all lymphomas [1, 2] with the classical type being the commonest
Chidamide inhibits the proliferation of Hodgkin lymphoma cell lines through apoptosis pathway
We demonstrated chidamide inhibits the proliferation of Hodgkin lymphoma cell lines through apoptosis pathway and arresting cell cycle in G0/G1 phase

Summary

Introduction

Hodgkin lymphoma (HL) is a well-established malignancy and accounts for about 8~13% of all lymphomas [1, 2] with the classical type being the commonest. Excessive activation of histone deacetylase (HDAC) and hyper-methylation of promoter region of tumor suppressor gene are two most studied aspects of epigenetic abnormalities in cancer. The selective class I HDAC inhibitor, has been approved for the treatment of peripheral T-cell lymphoma in China, but its activity on HL has not been tested yet. In vitro studies showed that Decitabine could inhibit the function of MYC gene by upregulating the expression of ID2 [16] and synergistically suppressing the proliferation of diffuse large B cell lymphoma cell lines with HDAC inhibitor Panobinostat [17]. The purpose of this study is to investigate the antitumor activity of chidamide and synergistic inhibition effects when combined with decitabine in HL cell lines

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Conclusion