Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas
Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas
复制标题
癌基因 HNF4A 谱系特异性表观基因组和基因组激活促进胃肠道腺癌。
DOI：
10.1158/0008-5472.can-20-0390
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发表时间：
2020-07-01
期刊：
影响因子：
11.2
通讯作者：
Lin, De-Chen
中科院分区：
文献类型：
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作者：
Pan, Jian;Silva, Tiago C.;Lin, De-Chen
胃肠道腺癌（GIAC）的管状胃肠道（GI）道，包括食管，胃，结肠和直肠包括大多数GI癌症和共享的基因组特征谱。然而，GIAC特有的统一表观基因组变化的特征很差。使用来自癌症基因组图谱的907个GIAC样本，我们将数学算法应用于大规模DNA甲基化组和转录组图谱，以重建转录因子（TF）网络，并确定在不同GIAC中共享的功能过度活跃的主调节因子（MR）TF列表。最佳候选人HNF4A以GIAC特异性方式表现出突出的基因组和表观基因组激活。HNF4A启动子和三个远端增强子元件之间的复杂相互作用由GIAC特异性MRTF（包括ELF3、GATA 4、GATA 6和KLF 5）协调。HNF4A还自我调节其自身的启动子和增强子。在功能上，HNF4A通过转录激活许多下游靶点（包括HNF1A和白细胞介素信号传导因子）以谱系特异性方式促进癌症增殖和存活。总体而言，我们的研究提供了新的见解GIAC特异性基因调控网络，并确定潜在的治疗策略对这些常见cancer.Significance：这些研究结果表明，GIAC特异性主调节转录因子控制HNF 4A通过三个远端增强子，以促进GIAC细胞增殖和生存。
Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract induding esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers.Significance: These findings show that GIAC-specific master regulatory transcription factors control HNF4A via three distal enhancers to promote GIAC cell proliferation and survival.