Abstract
The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells.
Highlights
The CCAAT box is an important element present in promoters and enhancers of eukaryotic genes
We focused on metabolic genes with the following strategy
(i) We analyzed the results of Affymetrix gene expression profilings of Hela-S3 cells inactivated of NFYA by shRNA interference [11] and performed additional profilings in epithelial HCT116 and H322 cells under identical conditions of NF-YA inactivation
Summary
The CCAAT box is an important element present in promoters and enhancers of eukaryotic genes. It is bound by the evolutionarily conserved NF-Y ( named CBF), a trimer formed by NF-YA, NF-YB and NF-YC. Yeast S. cerevisiae produces energy and ethanol through glycolysis and fermentation when grown in medium containing glucose; when challenged with non-fermentable carbon sources, yeast cells switch to oxygen-fueled metabolism, by activation of nuclear genes of the mitochondrial respiratory complexes. All these genes contain a CCAAT sequence in their regulatory
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