Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma
Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma
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DOI：
10.1172/jci87583
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发表时间：
2017-03-01
影响因子：
15.9
通讯作者：
Leone, Gustavo
中科院分区：
文献类型：
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作者：
Kent, Lindsey N.;Bae, Sooin;Leone, Gustavo
视网膜母细胞瘤 (RB) 肿瘤抑制途径的破坏，无论是通过上游调控元件的基因突变还是 RB1 本身的突变，被认为是癌症发生的必要事件。然而，RB 调节的 E2F 转录因子家族的基因改变并不常见，这使得人们对 E2F 在驱动癌症中的直接作用产生了怀疑。在这项工作中，对人类癌症的突变分析揭示了肝细胞癌 (HCC) 中 E2F1 和 E2F3 的拷贝数微妙但有影响力的增加。使用一系列功能丧失和获得功能的等位基因来调节 E2F 转录输出，我们发现 E2f1 或 E2f3b 中的拷贝数增加会导致小鼠出现剂量依赖性自发性 HCC，而无需其他器官的参与。相反，E2f1 或 E2f3b 的种系缺失（而非 E2f3a）可以保护小鼠免受 HCC 的侵害。染色质占据和转录组分析的组合图谱确定了 E2F1 和 E2F3B 驱动的转录程序，该程序与 HCC 的发生和进展相关。这些发现证明了 E2F 激活剂在人类癌症中的直接和细胞自主作用。
Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss-and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.