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EMBO J. 2014 Jun 17;33(12):1365-82. doi: 10.15252/embj.201386874. Epub 2014 May 16.

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Author information

1
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK vinny.zecchini@cruk.cam.ac.uk.
2
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
3
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
4
Department of Pathology, University of Cambridge, Cambridge, UK.
5
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
6
Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership University of Oslo and Oslo University Hospital, Oslo, Norway Department of Cancer Prevention and Urology, Institute of Cancer Research and Oslo University Hospital, Oslo, Norway.

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.

KEYWORDS:

Adaptor; hypoxia; metabolism; prostate; transcription

PMID:
24837709
PMCID:
PMC4194125
DOI:
10.15252/embj.201386874
[Indexed for MEDLINE]
Free PMC Article

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