Dual targeting of EZH2 and Histone Deacetylases in hematological malignancies promotes transcriptional and metabolic deregulation leading to ferroptosis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254725 | GEO | 2024/07/01
REPOSITORIES: GEO
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Project description:The methyltransferase EZH2 functions as the enzymatic component of the PRC2 complex, which deposits methyl groups on H3K27, leading to chromatin condensation and gene repression. Recent studies have shown that EZH2 can also act as a transcriptional modulator outside of the PRC2 complex independent of its methyltransferase activity. In this study, we first aimed to investigate the effects of EZH2 enzymatic inhibition versus protein degradation. We demonstrate that EZH2 degradation is more effective in blocking cellular proliferation compared to EZH2 enzymatic inhibition, and that EZH2 targeting upregulates the cholesterol biosynthesis pathway. Combined targeting of EZH2 and HDACs showed synergistic effects in a broader spectrum of hematological malignancies. Mechanistically, combined targeting of EZH2 and HDACs induced increased levels of H3K27 acetylation and strong upregulation of cholesterol biosynthesis. This leads to metabolic stress due to acetyl-CoA depletion, ultimately inducing ferroptotic cell death.
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Project description:The methyltransferase EZH2 functions as the enzymatic component of the PRC2 complex, which deposits methyl groups on H3K27, leading to chromatin condensation and gene repression. Recent studies have shown that EZH2 can also act as a transcriptional modulator outside of the PRC2 complex independent of its methyltransferase activity. In this study, we first aimed to investigate the effects of EZH2 enzymatic inhibition versus protein degradation. We demonstrate that EZH2 degradation is more effective in blocking cellular proliferation compared to EZH2 enzymatic inhibition, and that EZH2 targeting upregulates the cholesterol biosynthesis pathway. Combined targeting of EZH2 and HDACs showed synergistic effects in a broader spectrum of hematological malignancies. Mechanistically, combined targeting of EZH2 and HDACs induced increased levels of H3K27 acetylation and strong upregulation of cholesterol biosynthesis. This leads to metabolic stress due to acetyl-CoA depletion, ultimately inducing ferroptotic cell death.
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Project description:Dual targeting of EZH2 and Histone Deacetylases in hematological malignancies promotes transcriptional and metabolic deregulation leading to ferroptosis.
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Project description:Dual targeting of EZH2 and Histone Deacetylases in hematological malignancies promotes transcriptional and metabolic deregulation leading to ferroptosis. [ChIP-Seq]
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Project description:Dual targeting of EZH2 and Histone Deacetylases in hematological malignancies promotes transcriptional and metabolic deregulation leading to ferroptosis. [RNA-Seq]
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Project description:Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.
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