NF-YA Overexpression in Lung Cancer: LUSC

Abstract

The CCAAT box is recognized by the trimeric transcription factor NF-Y, whose NF-YA subunit is present in two major splicing isoforms, NF-YAl (“long”) and NF-YAs (“short”). Little is known about the expression levels of NF-Y subunits in tumors, and nothing in lung cancer. By interrogating RNA-seq TCGA and GEO datasets, we found that, unlike NF-YB/NF-YC, NF-YAs is overexpressed in lung squamous cell carcinomas (LUSC). The ratio of the two isoforms changes from normal to cancer cells, with NF-YAs becoming predominant in the latter. NF-YA increased expression correlates with common proliferation markers. We partitioned all 501 TCGA LUSC tumors in the four molecular cohorts and verified that NF-YAs is similarly overexpressed. We analyzed global and subtype-specific RNA-seq data and found that CCAAT is the most abundant DNA matrix in promoters of genes overexpressed in all subtypes. Enriched Gene Ontology terms are cell-cycle and signaling. Survival curves indicate a worse clinical outcome for patients with increasing global amounts of NF-YA; same with hazard ratios with very high and, surprisingly, very low NF-YAs/NF-YAl ratios. We then analyzed gene expression in this latter cohort and identified a different, pro-migration signature devoid of CCAAT. We conclude that overexpression of the NF-Y regulatory subunit in LUSC has the scope of increasing CCAAT-dependent, proliferative (NF-YAshigh) or CCAAT-less, pro-migration (NF-YAlhigh) genes. The data further reinstate the importance of analysis of single isoforms of TFs involved in tumor development.

NF-YA Overexpression in Lung Cancer: LUAD

“…The first, GSE40419, was derived from a Korean study of 89 LUAD [25]-mRNA levels of NF-YA were found to be substantially increased in tumors (p-value 10 −11 ); NF-YB was decreased (p value 10 −8 ) and NF-YC was unchanged ( Figure 1B). The second study was derived from data on 198 NSCLC patients, mostly from Sweden [24], which we previously reclassified using signature genes in 78 LUSC and 91 LUAD [23]; in the current study, we focused on LUAD samples, and showed that NF-YA, but not the HFD subunits, was globally increased ( Figure 1C). In conclusion, we confirmed NF-YA overexpression in LUAD, a decrease of NF-YB, and normal expression of NF-YC.…”

“…GSE81089 is a dataset of 198 NSCLC; using 42 genes validated classifier [27], we previously sub-classified samples in LUAD and LUSC [23]. This specifically identified 91 LUAD samples, which are analyzed in this study.…”

“…We used KOBAS 3.0 (http://kobas.cbi.pku.edu.cn/anno_iden.php) for pathway enrichment analysis using the ENTREZ gene IDs. The TFBS and de novo motif analysis were performed as in [22,23].…”

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

“…In endometrial tissues, the exclusive presence of NF-YAl observed in benign samples suggested that it may represent a marker of differentiation, in opposition to NF-YAs, which is expressed into cancer tissues and linked to poorly differentiated cells [26]. In breast and lung cancers, the ratio Cells 2020, 9, 760 4 of 28 between NF-YAl/NF-YAs isoforms is dramatically shifted towards NF-YAs [27,28]. Despite this, partitioning of breast tumors according to NF-YAl/NF-YAs ratio highlighted a unique category with a high NF-YAl/NF-YAs ratio, that is NF-YAl high /Claudin low subclass, composed by more aggressive tumors prone to metastasize [27].…”

“…NF-YAs high tumors are enriched in metabolism and cell-cycle up-regulated gene categories. In opposition, these genes are down-regulated in NF-YAl high tumors, characterized by the up-regulation of a promigration signature [28]. While NF-YAs directly activates cell cycle and metabolic genes, NF-YAl indirectly affects promigration genes.…”