Genome-wide Mapping of ARRB1 Reveals its Role as a HIF1A Transcriptional Co-regulator and Regulator of Cellular Metabolism [expression array]

Beta-arrestin 1 (ARRB1) has been implicated in transcriptional regulation as part of protein complexes bound to chromatin. Here we investigate its effect on transcription and its potential impact on prostate cancer. We report the first genome-wide mapping of chromatin binding for ARRB1 and combine it with expression array data to define its transcriptome. We identify Hypoxia Inducible Factor 1A (HIF1A) as a nuclear binding partner that recruits ARRB1 to promoter regions of HIF1A targets. We show that ARRB1 modulates HIF1A-dependent transcription and promotes a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. In addition, we show that ARRB1 plays an important role in neoplastic transformation, cell growth and resistance to hypoxic stress. This is the first example of an endocytic adaptor protein regulating metabolic pathways and implicates ARRB1 as a tumour promoter.

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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