NF-YAl drives EMT in Claudinlow tumours

Abstract

NF-Y is a trimeric transcription factor whose binding site -the CCAAT box- is enriched in cancer-promoting genes. The regulatory subunit, the sequence-specificity conferring NF-YA, comes in two major isoforms, NF-YA long (NF-YAl) and short (NF-YAs). Extensive expression analysis in epithelial cancers determined two features: widespread overexpression and changes in NF-YAl/NF-YAs ratios (NF-YAr) in tumours with EMT features. We performed wet and in silico experiments to explore the role of the isoforms in breast -BRCA- and gastric -STAD- cancers. We generated clones of two Claudinlow BRCA lines SUM159PT and BT549 ablated of exon-3, thus shifting expression from NF-YAl to NF-YAs. Edited clones show normal growth but reduced migratory capacities in vitro and ability to metastatize in vivo. Using TCGA, including upon deconvolution of scRNA-seq data, we formalize the clinical importance of high NF-YAr, associated to EMT genes and cell populations. We derive a novel, prognostic 158 genes signature common to BRCA and STAD Claudinlow tumours. Finally, we identify splicing factors associated to high NF-YAr, validating RBFOX2 as promoting expression of NF-YAl. These data bring three relevant results: (i) the definition and clinical implications of NF-YAr and the 158 genes signature in Claudinlow tumours; (ii) genetic evidence of 28 amino acids in NF-YAl with EMT-promoting capacity; (iii) the definition of selected splicing factors associated to NF-YA isoforms.

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“…5c). ChromVar analyses suggested a significant decrease of activity of fibrosis and EMT-related factors Twist1, Tcf12 and Nfya with age, along with increased activity of Hand2 94-96 ( Supplementary Fig. 5d and Supplementary Table 4e ).…”

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“…Oppositely, high levels of NF-YAl correlate with the overexpression of pro-migration genes and drive epithelial to mesenchymal transition (EMT) in aggressive tumors. 9,17,18 The detection and quantification of NF-YA isoforms in biopsies could improve the evaluation of the progression stage of cancers. In the literature, some examples of biosensors for the detection of transcription factors are reported.…”

“…Oppositely, high levels of NF-YAl correlate with the overexpression of pro-migration genes and drive epithelial to mesenchymal transition (EMT) in aggressive tumors. 9,17,18…”

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