Abstract
Nucleolin is an essential protein that plays important roles in the regulation of cell cycle and cell proliferation. Its expression is up regulated in many cancer cells but its molecular functions are not well characterized. Nucleolin is present in the nucleus where it regulates gene expression at the transcriptional and post-transcriptional levels. Using HeLa cells depleted in nucleolin we performed an mRNA and miRNA transcriptomics analysis to identify biological pathways involving nucleolin. Bioinformatic analysis strongly points to a role of nucleolin in lipid metabolism, and in many signaling pathways. Down regulation of nucleolin is associated with lower level of cholesterol while the amount of fatty acids is increased. This could be explained by the decreased and mis-localized expression of the transcription factor SREBP1 and the down-regulation of enzymes involved in the beta-oxidation and degradation of fatty acids. Functional classification of the miRNA-mRNA target genes revealed that deregulated miRNAs target genes involved in apoptosis, proliferation and signaling pathways. Several of these deregulated miRNAs have been shown to control lipid metabolism. This integrated transcriptomic analysis uncovers new unexpected roles for nucleolin in metabolic regulation and signaling pathways paving the way to better understand the global function of nucleolin within the cell.
Highlights
Nucleolin (NCL) is a highly conserved protein in eukaryotes with multiple functions in the cells[1]
NCL participates to the production of ribosomal RNA by RNA polymerase I (RNAPI), and a growing number of studies found NCL involved in the regulation of transcription by RNA polymerase II (RNAPII)[4]
NCL is one component of LR1, a B cell-specific transcription factor[13]; it was found in mantle cell lymphoma (MCL) to bind sites within the cyclin D1 gene and to activate transcription of this gene[14]
Summary
To gain a more global view on NCL function in the cell, a transcriptomic analysis of HeLa cells that have been depleted in NCL was performed. One of the strongest repressed gene in cells expressing low amount of NCL is CCNB1 coding for the G2/M specific cyclin B1 (Fig. 2B) This down regulation of CCNB1 mRNA level was confirmed by RT q-PCR (Fig. 2C) and western blot analysis of protein samples prepared from control and siRNA treated cells confirm the depletion of CCNB1 protein (Fig. 2D) upon NCL depletion. Our data agree and may provide a molecular mechanism with a recent observation that NCL targeting in retinoblastoma result in global lipid reduction[33] These data suggest that the over-expression of NCL protein in cancer cells probably participates in the increased metabolism required for the proliferation of tumor cells. This transcriptomic study paves the way to analyze more globally the cellular function of NCL
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