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

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.

Chidamide combined with traditional chemotherapy for primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma: A case report

“…Wei Guan et al [ 9 ] retrospectively analyzed 17 cases of refractory or relapsed T-lymphocytic lymphoma/leukemia (T-LBL/ALL) and found that chidamide has pleiotropic regulatory immune function and can enhance the sensitivity of tumor cells to chemotherapeutic drugs. Jiang et al [ 10 ] found that chidamide inhibited the proliferation and induced apoptosis of tumor cells and exerted potential anti-leukemia activity. Chidamide can also increase the chemosensitivity of tumor cells by disrupting the Smo/gli-1 pathway and the downstream signaling target p-AKT.…”

Inhibition of mitochondrial fission alters neo-intimal hyperplasia via PI3K/Akt signaling in arteriovenous fistulas

“…Vascular smooth muscle cell growth was assessed with the CCK8 assay kit (Dojindo, Japan), following the kit instructions. 27 Briefly, VSMCs were plated in 96-well plates, and treated with PDGF-BB (30 ng/mL, 24 h), Mdivi-1 (10 μM), PI3K inhibitor (LY294002, 10 μM), and an Akt1/2 kinase inhibitor (IH, 10 μM) for 60 min. After VSMCs were incubated with 10 μL of CCK8 solution for 30 min at 37°C, the absorbance of each well was measured at 450 nm using a spectrophotometer (Thermo Fisher Scientific, USA).…”

Synergistic effect of HDAC inhibitor Chidamide with Cladribine on cell cycle arrest and apoptosis by targeting HDAC2/c-Myc/RCC1 axis in acute myeloid leukemia

“…Chidamide (CHI) is a novel subtype-selective HDACi, that could selectively inhibit the activity of class I (HDAC1, 2, and 3) and class IIb (HDAC10) HDAC with a low concentration, which has been approved to treat peripheral T-cell lymphoma [ 4 ]. It has been reported that CHI could inhibit cell proliferation, induces G0/G1 arrest, increases apoptosis [ 5 , 6 ], and the chemosensitivity [ 7 , 8 ] alone or in combination with other drugs in AML.…”