Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells
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Supporting information
Author(s)
Type
Journal Article
Abstract
Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.
Date Issued
2015-10-19
Date Acceptance
2015-07-09
Citation
Oncogene, 2015, 35, pp.2766-2776
ISSN
1476-5594
Publisher
Nature Publishing Group
Start Page
2766
End Page
2776
Journal / Book Title
Oncogene
Volume
35
Copyright Statement
© 2015, Rights Managed by Nature Publishing Group
Sponsor
Cancer Research UK
Grant Number
C26587/A15115
Subjects
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status
Published