Gene regulatory network construction identified NFYA as a diffuse subtype-specific prognostic factor in gastric cancer

Cao, Bin; Zhao, Yu; Zhang, Zheng; Li, Hengcun; Xing, Jie; Guo, Shaodong; Qiu, Xintao; Zhang, Shutian; Min, Li; Zhu, Shoumin

doi:10.3892/ijo.2018.4519

Cited by 11 publications

(12 citation statements)

References 41 publications

(49 reference statements)

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“…The increased expression of NF-YA in epithelial tumors is becoming obvious, as other Authors have shown [ 19 , 20 , 21 , 22 , 23 ], and as we have progressively been reporting in our systematic TCGA-based analysis [ 24 , 25 , 26 , 27 ]. The results shown here further confirm the abundance of NF-Y sites (CCAAT) in the promoters of genes overexpressed in cancer, the increased expression of the “short” NF-YA in epithelial tumors and of “long” NF-YA in tumors expressing mesenchymal markers.…”

Section: Discussionsupporting

confidence: 69%

“…NF-Y has long been considered a ubiquitous transcription factor present at similar levels in normal and transformed cells; this view has largely changed, in part because of recent studies on the mRNA expression of its subunits in cancer. Data in ovarian [ 19 , 20 ], breast [ 21 ] and gastric [ 22 , 23 ] cancers indicated overexpression of NF-YA in tumors. Examination of the levels of NF-YA in cancer specimens present in The Cancer Genome Atlas (TCGA) by Firebrowse ( , accessed on 20 January 2020) suggested overexpression in epithelial tumors [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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NF-Y Subunits Overexpression in HNSCC

Bezzecchi

Bernardini

Ronzio

et al. 2021

Cancers

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NF-Y is the CCAAT-binding trimer formed by the histone fold domain (HFD), NF-YB/NF-YC and NF-YA. The CCAAT box is generally prevalent in promoters of “cancer” genes. We reported the overexpression of NF-YA in BRCA, LUAD and LUSC, and of all subunits in HCC. Altered splicing of NF-YA was found in breast and lung cancer. We analyzed RNA-seq datasets of TCGA and cell lines of head and neck squamous cell carcinomas (HNSCC). We partitioned all TCGA data into four subtypes, deconvoluted single-cell RNA-seq of tumors and derived survival curves. The CCAAT box was enriched in the promoters of overexpressed genes. The “short” NF-YAs was overexpressed in all subtypes and the “long” NF-YAl in Mesenchymal. The HFD subunits are overexpressed, except Basal (NF-YB) and Atypical (NF-YC); NF-YAl is increased in p53 mutated tumors. In HPV-positive tumors, high levels of NF-YAs, p16 and ΔNp63 correlate with better prognosis. Deconvolution of single cell RNA-seq (scRNA-seq) found a correlation of NF-YAl with Cancer Associated Fibroblasts (CAFs) and p-EMT cells, a population endowed with metastatic potential. We conclude that overexpression of HFD subunits and NF-YAs is protective in HPV-positive tumors; expression of NF-YAl is largely confined to mutp53 tumors and malignant p-EMT cells.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

NF-Y Subunits Overexpression in HNSCC

Bezzecchi

Bernardini

Ronzio

et al. 2021

Cancers

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“…Elevated expression of NF-YA, along with other TFs, was reported in Triple Negative Breast Cancers 14 . 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 .…”

Section: Introductionmentioning

confidence: 99%

Overexpression and alternative splicing of NF-YA in breast cancer

Dolfini

Andrioletti

Mantovani

2019

Sci Rep

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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.

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“…The inactivation of NF-YA by RNAi leads to cell-cycle arrest and apoptosis in different cellular contexts, and no cell line has ever been described lacking NF-Y activity. On the other hand, our knowledge about the actual expression levels of NF-Y subunits in human tumors is still at a rudimentary stage: elevated expression of NF-YA was reported in cohorts of epithelial ovarian cancer [16,17], triple negative breast cancers [18], gastric cancer [19,20], and of the NF-YC subunit in gliomas and colon adenocarcinomas [21,22]. We recently started to interrogate, both in quantitative and qualitative way, the large RNA-seq datasets of TCGA and, surprisingly, found that NF-YA is overexpressed in most tumors of epithelial origin.…”

Section: Introductionmentioning

confidence: 99%

NF-YA Overexpression in Lung Cancer: LUSC

Bezzecchi

Ronzio

Dolfini

et al. 2019

Genes

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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.

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Gene regulatory network construction identified NFYA as a diffuse subtype-specific prognostic factor in gastric cancer

Cited by 11 publications

References 41 publications

NF-Y Subunits Overexpression in HNSCC

NF-Y Subunits Overexpression in HNSCC

Overexpression and alternative splicing of NF-YA in breast cancer

NF-YA Overexpression in Lung Cancer: LUSC

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