Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome

Aoyama, Kazumasa; Oshima, Motohiko; Koide, Shuhei; Suzuki, Emi; Mochizuki-Kashio, Makiko; Kato, Yuko; Tara, Shiro; Sugiyama, Daisuke; Hiura, Nobuhiro; Nakajima‐Takagi, Yaeko; Sashida, Goro; Iwama, Atsushi

doi:10.1016/j.isci.2018.10.008

Cited by 20 publications

(23 citation statements)

References 39 publications

(55 reference statements)

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“…Previous studies have suggested that EZH1 augments and complements EZH2 activity and partially compensates for its loss in different contexts . We herein demonstrated that H3K27me3 levels were maintained or elevated after TAS‐117 treatment (see the data in Figure B,C).…”

Section: Resultssupporting

confidence: 68%

“…Despite the development of selective EZH2 inhibitors in clinical trials, it is clear that the inhibition of EZH2 alone is insufficient for the complete disruption of PRC2 oncogenic functions . Although inconsequential to EZH2 functions, EZH1 can augment and maintain PRC2 activities . We herein clearly demonstrated that EZH1 contributes to an important compensatory mechanism in MM.…”

Section: Discussionmentioning

confidence: 59%

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Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

et al. 2019

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Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3

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Section: Resultssupporting

confidence: 68%

Section: Discussionmentioning

confidence: 59%

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

et al. 2019

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“…As expected, EZH1 occupancy was increased at other non-fibrotic genes to maintain H3K27me3 levels (Fig. 2g,h), supporting previous reports of EZH1 compensation for EZH2 deficiency 27-29 .…”

Section: Mainsupporting

confidence: 91%

A polycomb-independent role of EZH2 in TGFβ1-damaged epithelium triggers a fibrotic cascade with mesenchymal cells

Kollak

et al. 2020

Preprint

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To restore organ homeostasis, a myriad of cell types need to activate rapid and transient programs to adjust cell fate decisions and elicit a collective behaviour. Characterisation of such programs are imperative to elucidate an organ’s regenerative capacity and its aberrant repair in disease. By modelling epithelial-mesenchymal crosstalk, we provide direct evidence for transforming growth factor β1 (TGFβ1)-damaged epithelium initiating a bi-directional fibrotic cascade with the mesenchyme. Strikingly, TGFβ1-damaged epithelia facilitates the release of Enhancer of Zester Homolog 2 (EZH2) from Polycomb Repressive Complex 2 (PRC2) to establish a novel fibrotic transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin. Perturbing this complex by disrupting epithelial EZH2 or actomyosin remodelling abrogates the fibrotic crosstalk. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve global H3K27me3 occupancy. Our results reveal an important non-canonical function of EZH2, paving the way for therapeutic interventions in fibrotic disease.

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“…Downregulation of EZH2 reduced the level of H3K27me3 in SKM-1 cells after intervention of EZH1 expression. EZH1 targets bivalent genes to sustain the self-renewal of stem cells in EZH2-de cient MDS [40]. Brie y, EZH2 regulated the level of H3K27me3, and EZH1 compensated for the effect of EZH2 deletion.…”

Section: Discussionmentioning

confidence: 99%

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

Zheng

et al. 2020

Preprint

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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.

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Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome

Cited by 20 publications

References 39 publications

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

A polycomb-independent role of EZH2 in TGFβ1-damaged epithelium triggers a fibrotic cascade with mesenchymal cells

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

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