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Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways

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机构: [1]Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [2]The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. [3]Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [4]Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada. [5]Department of Computer Science, University of Toronto, Toronto, ON, Canada. [6]Ontario Institute for Cancer Research, Toronto, ON, Canada. [7]Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [8]Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [9]The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, China. [10]Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada. [11]Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada. [12]Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [13]Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
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Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.© 2024. The Author(s).

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大类 | 1 区 综合性期刊
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第一作者机构: [1]Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [2]The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
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通讯机构: [1]Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [2]The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. [8]Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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