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Nuclear ARRB 1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer
Author(s) -
Zecchini Vincent,
Madhu Basetti,
Russell Roslin,
PértegaGomes Nelma,
Warren Anne,
Gaude Edoardo,
Borlido Joana,
Stark Rory,
IrelandZecchini Heather,
Rao Roheet,
Scott Helen,
Boren Joan,
Massie Charlie,
Asim Mohammad,
Brindle Kevin,
Griffiths John,
Frezza Christian,
Neal David E,
Mills Ian G
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201386874
Subject(s) - prostate cancer , hif1a , biology , microbiology and biotechnology , oxidative phosphorylation , cancer cell , endocytic cycle , cancer research , chemistry , cancer , biochemistry , cell , endocytosis , angiogenesis , genetics
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, ARRB 1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB 1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF 1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A ( SDHA ) and fumarate hydratase ( FH ) expression. ARRB 1‐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 ARRB 1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.