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Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells

Oncogene volume 35, pages 2766–2776 (2016)Cite this article

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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.

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Acknowledgements

HK, CK, GT and JE acknowledge support by the European Community’s Seventh Framework Programme—Health (FP7/2007-2013) project DETECTIVE (grant agreement number 266838). HK and JE are also supported by Cancer Research UK programme grant A15115. HK and GV are supported by the EC FP7/2007-2013 project Euro-MOTOR (grant agreement number 259867). CHL is supported by a UK Biotechnology and Biological Sciences Research Council (BBSRC) PhD studentship (grant number BB/F529270/1 for the Institute of Chemical Biology (Imperial College London) Doctoral Training Centre). YP is supported by a Royal Thai Government Scholarship. TY is supported by a UK MRC PhD studentship (Imperial College London Faculty of Medicine Doctoral Training Award). AB is supported by the EC FP7/2013-2018 project HeCaTos (grant agreement number 602156). We also acknowledge valuable discussions with Dr Charlotte Bevan, Professor Charles Coombes, Dr Jake Bundy, Professor Nigel Gooderham and Dr Tim Ebbels.

Author contributions

CK and HK conceived the project. CK, GV and HK prepared and wrote the final manuscript and figures with support from other authors. CK, GV and JE conducted cell experiments to confirm miR-22 regulation of target genes. GV established the luciferase reporter assays. GT, JE and GV conducted 13C labelling experiments. GT established all GC-MS protocols and conducted the modelling of isotopomer distributions. CHL conducted supporting metabolomic analysis. EN conducted the PLS modelling. TY and AB carried out confirmatory protein analyses. YP conducted the bioinformatic analysis of all patient data sets. CK conducted all other bioinformatic analyses. HK managed the project. All authors made a significant practical and intellectual contribution to the manuscript.

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Authors and Affiliations

  1. Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK

    C Koufaris, G N Valbuena, Y Pomyen, G D Tredwell, C-HE Lau, T Yang, A Benito, J K Ellis & H C Keun

  2. Department of Cytogenetics and Genomics, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

    C Koufaris

  3. Translational Research Unit, Chulabhorn Research Institute, Bangkok, Thailand

    Y Pomyen

  4. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

    E Nevedomskaya

  5. Centre for Systems Oncology and Cancer Innovation, Imperial College London, Hammersmith Hospital, London, UK

    H C Keun

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  1. C Koufaris
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Koufaris, C., Valbuena, G., Pomyen, Y. et al. Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells. Oncogene 35, 2766–2776 (2016). https://doi.org/10.1038/onc.2015.333

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