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Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer [ChIP-seq]

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. HIF1A is a major regulator of this process but activation of HIF1A 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 Hypoxia Inducible Factor 1A (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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55615 | GEO | 2014/11/26

SECONDARY ACCESSION(S): PRJNA240221

REPOSITORIES: GEO

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Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer [ChIP-seq]

Project description: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. HIF1A is a major regulator of this process but activation of HIF1A 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 Hypoxia Inducible Factor 1A (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. In an attempt to identify the ARRB1 cistrome in prostate cancer cells, C4-2 prostate cancer cells expressing endogenous levels of ARRB1 were used to ChIP for ARRB1, p300 (previously shown to interact with ARRB1within transcriptional complexes), RNA PolII and histone markers H3K4me1 and H4K4me3 (markers for enhancer and promoter regions, respectively). Cells were untreated and cultured in FBS supplemented with 10%FBS. In parallel, C4-2 cells stably expressing a nuclear form of ARRB1 (nucARRB1) were also used to ChIP the same complexes under the same conditions. Finally, human prostate tissue was used to ChIP for ARRB1 and histone markers.

2014-11-26 | E-GEOD-55615 | biostudies-arrayexpress

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

Project description: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. Gene expression of C4-2 cells stably overexpressing ARRB1-GFP or nuclear ARRB1-GFP fusion proteins were compared with the GFP empty vector control or parental C4-2 cell lines using the illumina expression array platform. There were three biological replicates for the control groups and two for each of the ARRB1 groups.

2014-11-26 | E-GEOD-55614 | biostudies-arrayexpress

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

2014-11-26 | GSE55614 | GEO

Homo sapiens

Project description:Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer [ChIP-seq]

| PRJNA240221 | ENA

Genome-wide mapping of HIF-2Î± binding under normoxia in human bronchial epithelial cells (BEAS-2B)

Project description:Growing number of cancer (stem) cells and stem cells were described to accommodate constituent active HIF-2Î± under normoxia. Previous study of hypoxia effect may have obscured some of normoxic HIF-2Î± functions as hypoxia inducible features. Our interest in study of protective potential of HIFs in lung cells led us to discover pseudohypoxia functions of HIF-2Î± under normoxia in human bronchial epithelial cells which exhibit pluripotency related markers and features. Our study provided perspective to pseudohypoxia functions of HIF-2Î± via enrichment of de novo motifs. In addition to the C-TAD, the N-TAD of HIF-2Î± was found to contribute to targeting on these non-canonical loci. Further elucidation of pseudohypoxia mechanism could resolve its implication of malignancy or pluripotency. We report globally mapped binding of HIF-2Î± under normoxia by using high throughput sequencing

2016-07-06 | E-GEOD-81635 | biostudies-arrayexpress

Genome-wide mapping of HIF-2α binding under normoxia in human bronchial epithelial cells (BEAS-2B)

Project description:Growing number of cancer (stem) cells and stem cells were described to accommodate constituent active HIF-2α under normoxia. Previous study of hypoxia effect may have obscured some of normoxic HIF-2α functions as hypoxia inducible features. Our interest in study of protective potential of HIFs in lung cells led us to discover pseudohypoxia functions of HIF-2α under normoxia in human bronchial epithelial cells which exhibit pluripotency related markers and features. Our study provided perspective to pseudohypoxia functions of HIF-2α via enrichment of de novo motifs. In addition to the C-TAD, the N-TAD of HIF-2α was found to contribute to targeting on these non-canonical loci. Further elucidation of pseudohypoxia mechanism could resolve its implication of malignancy or pluripotency.

2016-07-06 | GSE81635 | GEO

CDK8 ChIP-seq from HCT116 cells in normoxia and hypoxia

Project description:To test if CDK8 acts directly at HIF1A target genes, we performed ChIP-seq experiments in HCT116 cells under normoxic and hypoxic conditions.

2013-03-01 | GSE38258 | GEO

Project description:ARRB1 regulates prostate cancer cell metabolism

| PRJNA240220 | ENA

CDK8 ChIP-seq from HCT116 cells in normoxia and hypoxia

Project description:To test if CDK8 acts directly at HIF1A target genes, we performed ChIP-seq experiments in HCT116 cells under normoxic and hypoxic conditions. ChIP-seq for CDK8 versus Input under normoxia and 24hrs hypoxia (1% O2).

2013-03-01 | E-GEOD-38258 | biostudies-arrayexpress

PolyA RNAseq from HCT116 cells in normoxia and hypoxia

Project description:To determine the effects of depleting TIP60, CDK8, or HIF1A on the transcriptional response to hypoxia, we performed RNAseq analysis of four HCT116 colorectal carcinoma cell lines (shNT, HIF1A-/-, shTIP60 and shCDK8) in normoxic and hypoxic (24hrs, 1% O2) conditions. PolyA RNA for two independent biological replicates was purified from HCT116 cells stably expressing an shRNA against a non-targeting control (shNT), TIP60 (shTIP60) or CDK8 (shCDK8), or genetically deleted HIF1A (HIF1A-/-) subjected to 24hrs 1% O2 (hypoxia) or maintained under ambient oxygen (21%; normoxia) was sequenced on the Ion Torrent platform. Reads were aligned to the human genome and gene-level counts were used for differential expression analysis.

2016-06-02 | E-GEOD-68297 | biostudies-arrayexpress

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