NF-Y subunits overexpression in gastric adenocarcinomas (STAD)

Alberto Gallo,Eugenia Bezzecchi,Roberto Mantovani,Diletta Dolfini,Mirko Ronzio

doi:10.1038/s41598-021-03027-y

Alberto Gallo, Eugenia Bezzecchi + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-03027-y

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Journal: Scientific Reports	Publication Date: Dec 1, 2021
Citations: 8	License type: open-access

Affiliation: University of Milan

Abstract

NF-Y is a pioneer transcription factor—TF—formed by the Histone-like NF-YB/NF-YC subunits and the regulatory NF-YA. It binds to the CCAAT box, an element enriched in promoters of genes overexpressed in many types of cancer. NF-YA is present in two major isoforms—NF-YAs and NF-YAl—due to alternative splicing, overexpressed in epithelial tumors. Here we analyzed NF-Y expression in stomach adenocarcinomas (STAD). We completed the partitioning of all TCGA tumor samples (450) according to molecular subtypes proposed by TCGA and ACRG, using the deep learning tool DeepCC. We analyzed differentially expressed genes—DEG—for enriched pathways and TFs binding sites in promoters. CCAAT is the predominant element only in the core group of genes upregulated in all subtypes, with cell-cycle gene signatures. NF-Y subunits are overexpressed, particularly NF-YA. NF-YAs is predominant in CIN, MSI and EBV TCGA subtypes, NF-YAl is higher in GS and in the ACRG EMT subtypes. Moreover, NF-YAlhigh tumors correlate with a discrete Claudinlow cohort. Elevated NF-YB levels are protective in MSS;TP53+ patients, whereas high NF-YAl/NF-YAs ratios correlate with worse prognosis. We conclude that NF-Y isoforms are associated to clinically relevant features of gastric cancer.

Highlights

NF-Y is a pioneer transcription factor—TF—formed by the Histone-like NF-YB/NF-YC subunits and the regulatory NF-YA
We report the presence of CCAAT in commonly overexpressed genes and overexpression of NF-YA isoforms, as well as a prognostic value of their relative levels
CCAAT is enriched globally, and at the top of the TFBS list, when all upregulated genes are computed: it is the case of lung tumors[26,27]; in the second, the enrichment is found either in specific subtypes—iCluster 3 in HCC28—or only in differentially expressed genes (DEG) shared by all subtypes, as in BRCA25 and stomach adenocarcinomas (STAD), as shown here

Summary

Introduction

NF-Y is a pioneer transcription factor—TF—formed by the Histone-like NF-YB/NF-YC subunits and the regulatory NF-YA. Abbreviations TCGA The Cancer Genome Atlas ACRG Asian Cancer Research Group NF-YAl Nuclear factor Y subunit A isoform long NF-YAs Nuclear factor Y subunit A isoform short NF-YB Nuclear factor Y subunit B NF-YC Nuclear factor Y subunit C E2F E2 factor TF Transcription factor TFBS Transcription factors binding sites FDR False discovery rate HFD Histone fold domain STAD Stomach adenocarcinoma BRCA Breast carcinoma LUSC Lung squamous cells carcinoma LUAD Lung adenocarcinoma HCC Hepatocellular carcinoma HNSCC Head and neck squamous cells carcinoma CIN Chromosome instability EBV Epstein-Barr virus GS Genomically stable MSI MicroSatellite instability EMT Endothelial to mesenchymal transition MSS MicroSatellite stable TP53 Tumor protein 53 TIC Tumor-initiating cells DEG Differentially expressed genes PFI Progression free interval. This involves the glutamine-rich trans-activation domains (TADs), while the subunits-interaction and DNA-binding domains are common to all isoforms

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Conclusion