Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

Vincent Zecchini, Basetti Madhu, Roslin Russell, Nelma Pértega-Gomes, Anne Warren, Edoardo Gaude, Joana Borlido, Rory Stark, Heather Ireland-Zecchini, Roheet Rao, Helen Scott, Joan Boren, Charlie Massie, Mohammad Asim, Kevin Brindle, John Griffiths, Christian Frezza, David E Neal, Ian G Mills

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)
234 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)1365-82
Number of pages18
JournalThe EMBO Journal
Volume33
Issue number12
Early online date16 May 2014
DOIs
Publication statusPublished - 17 Jun 2014

Keywords

  • Arrestins
  • Chromatin Immunoprecipitation
  • Fluorescent Antibody Technique
  • Fumarate Hydratase
  • Gas Chromatography-Mass Spectrometry
  • Gene Expression Profiling
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Immunohistochemistry
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolic Networks and Pathways
  • Metabolomics
  • Models, Biological
  • Prostatic Neoplasms
  • RNA Interference
  • Succinate Dehydrogenase
  • Tissue Array Analysis

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