Transcriptomics

Dataset Information

39

Response to a LNA miR-92a inhibitor in immortalized human bronchial epithelial cells.


ABSTRACT: Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically-targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We utilized a library of oligonucleotide inhibitors to microRNAs, a class of post-transcriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in NSCLC. Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific down-regulation of the miR-17~92 polycistron, and this down-regulation was toxic only in the context of p53 loss. Mechanistic studies indicated the selective toxicity of miR-17~92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1; a rate limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach utilized in this study can identify clinically relevant synthetic lethal interactions, and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients. 2 cell lines, 2 conditions per cell line, 3 replicates per condition, RNA collected 48 hours post transfection

ORGANISM(S): Homo sapiens  

SUBMITTER: Alexander Pertsemlidis  Michael A White    

PROVIDER: E-GEOD-64007 | ArrayExpress| 2015-01-02

SECONDARY ACCESSION(S): GSE64007PRJNA269737

REPOSITORIES: GEO, ArrayExpress

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