EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia

Abstract

ObjectiveMyelodysplastic syndrome (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells and may develop to acute myeloid leukemia (AML). We investigated the mechanism of histone methyltransferases EZH2/EHMT2 during the transformation of MDS to AML.MethodsExpression of EZH2/EHMT2 in MDS/AML patients and in NHD13 mice was detected. EZH2 and EHMT2 were silenced or overexpressed in SKM-1 cells to evaluate cell proliferation and cycle. Levels of DLX5, H3K27me3 and H3K9me2 were detected. The binding of DLX5 promoter region to H3K27me3 and H3K9me2 was examined. Levels of H3K27me3/H3K9me2 in cells were decreased by EZH2/EHMT2 inhibitors, and then changes of DLX5 expression and cell proliferation were observed.ResultsEZH2 was poorly expressed in MDS patients but highly expressed in MDS-AML patients. EHMT2 was elevated in both MDS and MDS-AML patients. EZH2 expression was reduced and EHMT2 expression was promoted in NHD13 mice. NHD13 mice with overexpressing EZH2 or EHMT2 transformed into AML more quickly. Intervention of EZH2 or EHMT2 inhibited SKM-1 cell proliferation and promoted DLX5 expression. Both silencing EZH1 and EZH2 in SKM-1 cells, the H3K27me3 level was decreased. EZH2 silencing repressed the proliferation of SKM-1 cells. The transcription level of DLX5 in SKM-1 cells was inhibited by H3K27me3 and H3K9me2. Enhanced DLX5 expression restrained the proliferation of SKM-1 cells.ConclusionEZH2/EHMT2 catalyzed H3K27me3/H3K9me2 to inhibit the transcription of DLX5, thus promoting the transformation from MDS to AML.