Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

ARRB1 regulates prostate cancer cell metabolism

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Silvia Halim

PROVIDER: E-GEOD-55616 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Zecchini Vincent V Madhu Basetti B Russell Roslin R Pértega-Gomes Nelma N Warren Anne A Gaude Edoardo E Borlido Joana J Stark Rory R Ireland-Zecchini Heather H Rao Roheet R Scott Helen H Boren Joan J Massie Charlie C Asim Mohammad M Brindle Kevin K Griffiths John J Frezza Christian C Neal David E DE Mills Ian G IG

The EMBO journal 20140516 12

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 ...[more]

PMID: 24837709

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Project description:Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in-silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analysed in-vitro and in-vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, DBP and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2, which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

Dataset Information

ARRB1 regulates prostate cancer cell metabolism

Publications

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

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