ArticleNeuro-oncology2024
Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.
Article in Neuro-oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 37 citations in OpenAlex.
- Single-cell and longitudinal transcriptomics-guided engineering of FZD1-targeting precision nanotherapy against osteosarcoma cancer stem cells.Bioactive materials · 2026Article
- The Sirtuin Network: Linking NADDiabetes/metabolism research and reviews · 2026Review
- ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma pathogenesis.Nucleic acids research · 2026Article
- Cellular senescence in cancer: from mechanism paradoxes to precision therapeutics.Molecular cancer · 2025Review
- Sirtuins in Central Nervous System Tumors-Molecular Mechanisms and Therapeutic Targeting.Cells · 2025Review
- Phase separated condensates of ATRX regulate neural progenitor identity.Nature communications · 2025Article
- G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target α-thalassemia/mental retardation X-linked-deficient malignant glioma.Neuro-oncology · 2025Article
- Targeting treatment resistance: unveiling the potential of RNA methylation regulators and TG-101,209 in pan-cancer neoadjuvant therapy.Journal of experimental & clinical cancer research : CR · 2024Article
- Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis.Acta neuropathologica communications · 2024Article
- SIRT2 inhibition as the Achilles' heel of ATRX-deficient gliomas.Neuro-oncology · 2024Article
- Mutant ATRX: pathogenesis of ATRX syndrome and cancer.Frontiers in molecular biosciences · 2024Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundFunctional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.
methodsWe utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).
resultsCMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition.
conclusionsOur findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.
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