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.
Highlights
Beta-arrestin1 (ARRB1) is a ubiquitously expressed adaptor protein with a wide range of cellular and molecular functions (Lefkowitz &Shenoy, 2005)
We show that ARRB1 physically occupies the promoter regions and modulates the expression of genes involved in cellular metabolism
We report a nuclear physical interaction between ARRB1 and hypoxia-inducible factor 1A (HIF1A) in prostate cancer cells and show that it occurs at the chromatin level, where recruitment of ARRB1 to hypoxia response elements (HRE) at functional promoters of HIF1A targets upon hypoxia is HIF1A dependent
Summary
Beta-arrestin (ARRB1) is a ubiquitously expressed adaptor protein with a wide range of cellular and molecular functions (Lefkowitz &Shenoy, 2005). Hypoxia inhibits prolyl hydroxylation resulting in stabilisation of HIF1A upon which it can translocate into the nucleus and heterodimerise with HIF1B to form a functional transcription factor (TF) that binds to specific promoter regions to activate the transcription of its target genes (Semenza, 2007b). Hypoxic stabilisation of HIF1A induces a switch in cellular metabolism via transcriptional activation of a plethora of metabolic genes that results in increased glycolysis and reduced mitochondrial function (Semenza, 2007c, 2010). This metabolic reprogramming, termed the Warburg effect, allows cancer cells to meet the increase in biomass production that is required to sustain their rapid proliferation
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