Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

• Vincent Zecchini ^[3] ; Basetti Madhu ^[3] ; Roslin Russell ^[3] ; Nelma Pértega-Gomes ^[1] ; Anne Warren ^[2] ; Edoardo Gaude ^[4] ; Joana Borlido ^[3] ; Rory Stark ^[3] ; Heather Ireland-Zecchini ^[3] ; Roheet Rao ^[3] ; Helen Scott ^[3] ; Joan Boren ^[3] ; Charlie Massie ^[3] ; Mohammad Asim ^[3] ; Kevin Brindle ^[3] ; John Griffiths ^[3] ; Christian Frezza ^[4] ; David E Neal ^[3] ; Ian G Mills ^[5]
  1. [1] Universidade do Minho

     Universidade do Minho

     Braga (São José de São Lázaro), Portugal

     
  2. [2] University of Cambridge

     University of Cambridge

     Cambridge District, Reino Unido

     
  3. [3] 1 Department of CRUK, CRUK Cambridge Institute, University of Cambridge Cambridge, UK
  4. [4] 4 Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge Cambridge, UK
  5. [5] 5 Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital Oslo, Norway; 6 Department of Cancer Prevention and Urology, Institute of Cancer Research and Oslo University Hospital Oslo, Norway

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 12, 2014, págs. 1365-1382
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.