Abstract
NF-Y is a CCAAT-binding trimeric transcription factor, whose regulome, interactome and oncogenic potential point to direct involvement in cellular transformation. Yet little is known about the levels of NF-Y subunits in tumors. We focused on breast carcinomas, and analyzed RNA-Seq datasets of TCGA and 54 BRCA cell lines at gene and isoforms level. We partitioned all tumors in the four major subclasses. NF-YA, but not histone-fold subunits NF-YB/NF-YC, is globally overexpressed, correlating with the proliferative Ki67 marker and a common set of 840 genes, with cell-cycle, metabolism GO terms. Their promoters are enriched in NF-Y, GC-rich and E2F sites. Surprisingly, there is an isoform switch, with the “short” isoform -NF-YAs- becoming predominant in tumors. E2F genes are also overexpressed in BRCA, but no switch in isoforms is observed. In Basal-like Claudinlow cell lines and tumors, expression of NF-YAl -long- isoform is high, together with 11 typical EMT markers and low levels of basal Keratins. Analysis of Progression-Free-Intervals indicates that tumors with unbalance of NF-YA isoforms ratios have worst clinical outcomes. The data suggest that NF-YA overexpression increases CCAAT-dependent, pro-growth genes in BRCA. NF-YAs is associated with a proliferative signature, but high levels of NF-YAl signal loss of epithelial features, EMT and acquisition of a more aggressive behavior in a subset of Claudinlow Basal-like tumors.
Highlights
NF-Y is a CCAAT-binding trimeric transcription factor, whose regulome, interactome and oncogenic potential point to direct involvement in cellular transformation
The analysis was limited to 18 tumor types and the results are shown in Fig. S1 as FPKMs box plots of NF-YA, NF-YB and NF-YC
The increase is robust in epithelial tumors: carcinomas of breast (BRCA), colon (COAD), rectum (READ), stomach (STAD), liver (LIHC), prostate (PRAD), uterine (UCEC), head and neck squamous cells (HNCC), cholangiocarcinoma (CHOL), lung adenocarcinoma (LUAD) and squamous cells carcinoma (LUSC)
Summary
NF-Y is a CCAAT-binding trimeric transcription factor, whose regulome, interactome and oncogenic potential point to direct involvement in cellular transformation. NF-YA, but not histone-fold subunits NF-YB/NF-YC, is globally overexpressed, correlating with the proliferative Ki67 marker and a common set of 840 genes, with cell-cycle, metabolism GO terms Their promoters are enriched in NF-Y, GC-rich and E2F sites. Microarrays profiling of genes overexpressed in tumor vs normal cells found cancer “signature” genes and TFBSs -Transcription Factor Binding Sites- searches identified CCAAT as overrepresented in their promoters (Reviewed in Ref.[7]). High levels of NF-YA mRNA were found in the “diffuse” type of gastric cancer[19], and of the NF-YC protein in gliomas[20] and colon adenocarcinomas[21] To close this gap in our knowledge of NF-Y biology, we analyzed the mRNA levels of NF-Y subunits in human tumor samples, both in quantitative and qualitative terms, by interrogating large-scale RNA-Seq datasets of TCGA.
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