1. Academic Validation
  2. Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

  • J Transl Med. 2021 Mar 21;19(1):117. doi: 10.1186/s12967-021-02789-3.
Xuejie Jiang 1 Ling Jiang 2 Jiaying Cheng 2 Fang Chen 2 Jinle Ni 2 Changxin Yin 2 Qiang Wang 2 Zhixiang Wang 2 Dan Fang 2 Zhengshan Yi 2 Guopan Yu 2 Qingxiu Zhong 3 Bing Z Carter 4 Fanyi Meng 5 6
Affiliations

Affiliations

  • 1 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. jxj3331233@163.com.
  • 2 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 3 Department of Hematology, Kanghua Hospital, Dongguan, 523080, Guangdong, China.
  • 4 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. mengfu@medmail.com.cn.
  • 6 Department of Hematology, Kanghua Hospital, Dongguan, 523080, Guangdong, China. mengfu@medmail.com.cn.
Abstract

Background: Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML.

Methods: Cell growth was assessed with CCK-8 assay, and Apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models.

Results: In this study, we investigated the antileukemia effects of HDAC Inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo.

Conclusions: Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.

Keywords

Chemosensitivity; Chidamide; EZH2; Leukemia; Smo/Gli-1.

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