Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20133, Milano, Italy.
Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, 72076, Tübingen, Germany.
Sci Rep. 2019 Sep 10;9(1):12955. doi: 10.1038/s41598-019-49297-5.
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 Claudin 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 Claudin Basal-like tumors.
NF-Y 是一种 CCAAT 结合的三聚体转录因子，其调节组、相互作用组和致癌潜能表明其直接参与细胞转化。然而，关于肿瘤中 NF-Y 亚基的水平知之甚少。我们专注于乳腺癌，并在基因和异构体水平上分析了 TCGA 和 54 个 BRCA 细胞系的 RNA-Seq 数据集。我们将所有肿瘤分为四个主要亚类。NF-YA，但不是组蛋白折叠亚基 NF-YB/NF-YC，全局过表达，与增殖标志物 Ki67 和一组共同的 840 个基因相关，具有细胞周期、代谢 GO 术语。它们的启动子富含 NF-Y、富含 GC 和 E2F 位点。令人惊讶的是，存在一种异构体转换，“短”异构体-NF-YAs-在肿瘤中占主导地位。E2F 基因在 BRCA 中也过表达，但没有观察到异构体转换。在基底样 Claudin 细胞系和肿瘤中，NF-YAl-长异构体的表达较高，同时表达 11 种典型的 EMT 标志物和基底角蛋白水平较低。无进展间隔期分析表明，NF-YA 异构体比率失衡的肿瘤具有最差的临床结局。数据表明，NF-YA 过表达增加了 BRCA 中 CCAAT 依赖性、促生长基因。NF-YAs 与增殖特征相关，但 NF-YAl 水平高表明上皮特征丧失、EMT 以及 Claudin 基底样肿瘤亚组获得更具侵袭性的行为。
