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ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.
Lu, Yuting; Travnickova, Jana; Badonyi, Mihaly; Rambow, Florian; Coates, Andrea; Khan, Zaid; Marques, Jair; Murphy, Laura C; Garcia-Martinez, Pablo; Marais, Richard; Louphrasitthiphol, Pakavarin; Chan, Alex H Y; Schofield, Christopher J; von Kriegsheim, Alex; Marsh, Joseph A; Pavet, Valeria; Sansom, Owen J; Illingworth, Robert S; Patton, E Elizabeth.
Afiliación
  • Lu Y; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Travnickova J; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Badonyi M; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Rambow F; Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, 45131 Essen, Germany; University of Duisburg-Essen, 45141 Essen, Germany.
  • Coates A; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Khan Z; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Marques J; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Murphy LC; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Garcia-Martinez P; Insitute of Genetics and Cancer, The Univeristy of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Marais R; Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK; Oncodrug Ltd, Alderley Park, Macclesfield SK10 4TG, UK.
  • Louphrasitthiphol P; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.
  • Chan AHY; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 5JJ, UK.
  • Schofield CJ; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 5JJ, UK.
  • von Kriegsheim A; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Marsh JA; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Pavet V; Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK; Cancer Research UK Beatson Institute, CRUK Scotland Centre, Garscube Estate, Switchback Road, Bearsden Glasgow G61 1BD, UK.
  • Sansom OJ; Cancer Research UK Beatson Institute, CRUK Scotland Centre, Garscube Estate, Switchback Road, Bearsden Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Glasgow G12 0ZD, UK.
  • Illingworth RS; Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK.
  • Patton EE; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address: e.patton@ed.ac.uk.
Cell Rep ; 43(7): 114406, 2024 Jul 23.
Article en En | MEDLINE | ID: mdl-38963759
ABSTRACT
Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pez Cebra / Acetaldehído / Melanoma Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pez Cebra / Acetaldehído / Melanoma Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos