Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.
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.
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK vinny.zecchini@cruk.cam.ac.uk.
Vincent
V
Zecchini
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Basetti
B
Madhu
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Roslin
R
Russell
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
Nelma
N
Pértega-Gomes
Department of Pathology, University of Cambridge, Cambridge, UK.
Anne
A
Warren
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
Edoardo
E
Gaude
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Joana
J
Borlido
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Rory
R
Stark
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Heather
H
Ireland-Zecchini
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Roheet
R
Rao
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Helen
H
Scott
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Joan
J
Boren
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Charlie
C
Massie
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Mohammad
M
Asim
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Kevin
K
Brindle
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
John
J
Griffiths
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
Christian
C
Frezza
Department of CRUK, CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
David E
DE
Neal
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.
Ian G
IG
Mills
D019390:Arrestins / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D005649:Fumarate Hydratase / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055432:Metabolomics; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D034622:RNA Interference; D013385:Succinate Dehydrogenase / Q000378:metabolism; D046888:Tissue Array Analysis; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D019390:Arrestins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase
Adaptor; hypoxia; metabolism; prostate; transcription