VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
复制标题
DOI：
10.1158/2159-8290.cd-17-0375
复制
发表时间：
2017-11-01
期刊：
影响因子：
28.2
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Yao, Xiaosai;Tan, Jing;Tan, Patrick
透明细胞肾细胞癌（ccRCC）的蛋白质编码突变已经被广泛表征，通常涉及von Hippel-Lindau （VHL）肿瘤抑制因子的失活。然而，非编码顺式调控畸变在ccRCC肿瘤发生中的作用仍不清楚。通过分析10对原发肿瘤/正常配对和9个细胞系的79种染色质谱，我们观察到ccRCC中普遍存在增强子功能障碍，同源增强子靶基因与恶性肿瘤的组织特异性方面相关。超增强子分析鉴定ZNF395是一种ccrcc特异性和vhl调控的主调控因子，其缺失可在体外和体内几乎完全消除肿瘤。与启动子相比，VHL缺失主要驱动增强子/超增强子解除管制，在ccRCC标志基因附近获得活性增强子标记（H3K27ac, H3K4me1）。从机制上说，VHL缺失稳定了HIF2 α - hif1 β异源二聚体在增强子上的结合，随后招募组蛋白乙酰转移酶p300，而不会明显影响先前存在的启动子-增强子相互作用。因此，亚型特异性驱动突变（如VHL）可能通过调节表观基因组景观和癌症基因表达，在ccRCC中传播独特的致病依赖性。意义：ccRCC的综合表观基因组分析建立了体细胞改变的顺式调控元件的概要，揭示了新的潜在靶点，包括ccRCC主调控因子ZNF395。VHL缺失是ccRCC的一个特征事件，它会导致普遍的增强子功能障碍，以增强子为中心的HIF2 α结合，并在已有的谱系特异性启动子-增强子复合物中募集组蛋白乙酰转移酶p300。(c) 2017 aacr。
Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2 alpha-HIF1 beta heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.SIGNIFICANCE: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2 alpha and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. (C) 2017 AACR.