Overexpression and alternative splicing of NF-YA in breast cancer
Overexpression and alternative splicing of NF-YA in breast cancer
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DOI：
10.1038/s41598-019-49297-5
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发表时间：
2019-09-10
影响因子：
4.6
通讯作者：
Mantovani, Roberto
中科院分区：
文献类型：
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作者：
Dolfini, Diletta;Andrioletti, Valentina;Mantovani, Roberto
NF-Y是一种与CCAAT结合的三聚体转录因子，其调节子组、相互作用子组和致癌潜能直接参与细胞转化，但其在肿瘤中的表达水平尚不清楚。我们以乳腺癌为研究对象，在基因和亚型水平上分析了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，而不是组蛋白折叠亚基NF-YB/NF-YC，是全球过度表达，与增殖Ki 67标记和一组共同的840个基因，细胞周期，代谢GO术语。它们的启动子富含NF-Y、富含GC和E2 F位点。令人惊讶的是，有一个亚型开关，与“短”亚型-NF-YAs-成为肿瘤中占主导地位。E2 F基因在BRCA中也过表达，但未观察到亚型转换。在基底样紧密连接蛋白（低）细胞系和肿瘤中，NF-YAI -long-同种型的表达高，以及11种典型的EMT标志物和低水平的基底角蛋白。无进展间期分析表明，NF-YA亚型比例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BRCA中CCAAT依赖性促生长基因。NF-YAs与增殖特征相关，但高水平的NFYAI表明上皮特征的丧失、EMT以及Claudin（低）基底细胞样肿瘤子集中更具攻击性行为的获得。
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(low) cell lines and tumors, expression of NF-YAI -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 N F-YA overexpression increases CCAAT-dependent, pro-growth genes in BRCA. NF-YAs is associated with a proliferative signature, but high levels of NFYAI signal loss of epithelial features, EMT and acquisition of a more aggressive behavior in a subset of Claudin(low) Basal-like tumors.