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) histone deacetylases (HDACs) reciprocally regulate acetylation deacetylation nuclear histones. Aberrant activation HDACs results uncontrolled proliferation blockade differentiation, HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, apoptosis evaluated by flow cytometry AML cell lines CD45 + CD34 CD38- cells from patient samples after staining Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 silenced short hairpin RNA (shRNA) or overexpressed lentiviral transfection. Changes signaling pathways were detected western blotting. The effect chidamide EZH2-specific shRNA (shEZH2) combination adriamycin studied vivo leukemia-bearing nude mouse models. Results In this study, we antileukemia effects inhibitor its combinatorial activity cytotoxic agent cells. We demonstrated that suppressed levels EZH2, H3K27me3 DNMT3A, exerted potential increased sensitivity to through disruption Smo/Gli-1 pathway downstream target p-AKT stem/progenitor addition decreasing either pharmacologically genetically shEZH2 vitro vivo. Conclusions Inhibition increases chemosensitivity (Fig. 5). These findings support rational inhibitors chemotherapy for treatment