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

doi:10.15252/embj.201386874

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

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

298 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 language	English
Pages (from-to)	1365-82
Number of pages	18
Journal	The EMBO Journal
Volume	33
Issue number	12
Early online date	16 May 2014
DOIs	https://doi.org/10.15252/embj.201386874
Publication status	Published - 17 Jun 2014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.15252/embj.201386874

Nuclear ARRB1 induces
© The Authors, 2014 This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.93 MB

Ian Mills
- I.Millsqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Professor
- The Johnston Cancer Research Centre
Person: Academic

Cite this

Zecchini, V., Madhu, B., Russell, R., Pértega-Gomes, N., Warren, A., Gaude, E., Borlido, J., Stark, R., Ireland-Zecchini, H., Rao, R., Scott, H., Boren, J., Massie, C., Asim, M., Brindle, K., Griffiths, J., Frezza, C., Neal, D. E., & Mills, I. G. (2014). Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. The EMBO Journal, 33(12), 1365-82. https://doi.org/10.15252/embj.201386874

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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.",

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author = "Vincent Zecchini and Basetti Madhu and Roslin Russell and Nelma P{\'e}rtega-Gomes and Anne Warren and Edoardo Gaude and Joana Borlido and Rory Stark and Heather Ireland-Zecchini and Roheet Rao and Helen Scott and Joan Boren and Charlie Massie and Mohammad Asim and Kevin Brindle and John Griffiths and Christian Frezza and Neal, \{David E\} and Mills, \{Ian G\}",

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month = jun,

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doi = "10.15252/embj.201386874",

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Zecchini, V, Madhu, B, Russell, R, Pértega-Gomes, N, Warren, A, Gaude, E, Borlido, J, Stark, R, Ireland-Zecchini, H, Rao, R, Scott, H, Boren, J, Massie, C, Asim, M, Brindle, K, Griffiths, J, Frezza, C, Neal, DE & Mills, IG 2014, 'Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer', The EMBO Journal, vol. 33, no. 12, pp. 1365-82. https://doi.org/10.15252/embj.201386874

TY - JOUR

T1 - Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

AU - Zecchini, Vincent

AU - Madhu, Basetti

AU - Russell, Roslin

AU - Pértega-Gomes, Nelma

AU - Warren, Anne

AU - Gaude, Edoardo

AU - Borlido, Joana

AU - Stark, Rory

AU - Ireland-Zecchini, Heather

AU - Rao, Roheet

AU - Scott, Helen

AU - Boren, Joan

AU - Massie, Charlie

AU - Asim, Mohammad

AU - Brindle, Kevin

AU - Griffiths, John

AU - Frezza, Christian

AU - Neal, David E

AU - Mills, Ian G

PY - 2014/6/17

Y1 - 2014/6/17

N2 - 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.

AB - 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.

KW - Arrestins

KW - Chromatin Immunoprecipitation

KW - Fluorescent Antibody Technique

KW - Fumarate Hydratase

KW - Gas Chromatography-Mass Spectrometry

KW - Gene Expression Profiling

KW - Humans

KW - Hypoxia-Inducible Factor 1, alpha Subunit

KW - Immunoblotting

KW - Immunohistochemistry

KW - Magnetic Resonance Spectroscopy

KW - Male

KW - Metabolic Networks and Pathways

KW - Metabolomics

KW - Models, Biological

KW - Prostatic Neoplasms

KW - RNA Interference

KW - Succinate Dehydrogenase

KW - Tissue Array Analysis

U2 - 10.15252/embj.201386874

DO - 10.15252/embj.201386874

M3 - Article

C2 - 24837709

SN - 0261-4189

VL - 33

SP - 1365

EP - 1382

JO - The EMBO Journal

JF - The EMBO Journal

IS - 12

ER -

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

Abstract

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Keywords

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Ian Mills

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