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Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
Siddaway, Robert; Canty, Laura; Pajovic, Sanja; Milos, Scott; Coyaud, Etienne; Sbergio, Stefanie-Grace; Vadivel Anguraj, Arun Kumaran; Lubanszky, Evan; Yun, Hwa Young; Portante, Alessia; Carette, Sheyenne; Zhang, Cunjie; Moran, Michael F; Raught, Brian; Campos, Eric I; Hawkins, Cynthia.
Afiliación
  • Siddaway R; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Canty L; Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • Pajovic S; Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
  • Milos S; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Coyaud E; Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • Sbergio SG; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Vadivel Anguraj AK; Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • Lubanszky E; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Yun HY; Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • Portante A; Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON, M5G 1L7, Canada.
  • Carette S; Université de Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, 59000, Lille, France.
  • Zhang C; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Moran MF; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • Raught B; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • Campos EI; Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • Hawkins C; The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
Acta Neuropathol ; 144(5): 1027-1048, 2022 11.
Article en En | MEDLINE | ID: mdl-36070144
ABSTRACT
Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histonas / Glioma Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Acta Neuropathol Año: 2022 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histonas / Glioma Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Acta Neuropathol Año: 2022 Tipo del documento: Article País de afiliación: Canadá