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

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.

High Expression of CPT1A Predicts Adverse Outcomes: A Potential Therapeutic Target for Acute Myeloid Leukemia

“…miR-22 could repress fatty acid synthesis and was an important regulator of lipid and folate metabolism in breast cancer cells (Koufaris et al, 2016). miR-27a was reported to accelerate adipolysis releasing significantly more glycerol and free fatty acids (Wang et al, 2011).…”

Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

“…The high expression of MTHFD2 in breast cancer, as well as the association between the levels of this enzyme and poor patient prognosis, demonstrate that altered function of this enzyme confers selective advantages to tumors 2,10,12,13 . However, recent data indicate that MTHFD2 also possesses non-metabolic functions 16 .…”

“…Recent studies have found a significant association between mRNA expression 10,11 and protein expression of MTHFD2 in large cohorts of breast cancer patients 13 .…”

“…We and others have previously reported that MTHFD2 is under the regulation of two miRNAs that are frequently deregulated in cancer, miR-9 and miR-22 9,10 .…”

Coordinated Regulation of Cap-Dependent Translation and MicroRNA Function by Convergent Signaling Pathways

“…Moreover, a miR-22 knockout mouse model was readily available. Activation of miR-22 knockout T cells resulted in significant increases in expression of miR-22 target genes Acly (26), Pten (27), and Tet2 (28), a trend toward increased expression of putative miR-22 target genes Ets1 and Serpinb9 (Fig. 2C), and no effect on expression of a control gene (Sdha) lacking miR-22 seed sites (see Fig.…”