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 HIF2α–HIF1β 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 HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR.

See related commentary by Ricketts and Linehan, p. 1221.

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透明细胞肾细胞癌（ccRCC）中的蛋白质编码突变已得到广泛表征，通常涉及灭活von Hippel-Lindau（VHL）肿瘤抑制因子。但是，尚不清楚在ccRCC肿瘤发生过程中非编码顺式调节畸变的作用。分析79个染色质图谱中的10个原发性肿瘤/正常对和9个细胞系，我们观察到了ccRCC中普遍存在的增强子功能异常，以及与恶性组织特定方面相关的同源增强子靶基因。Superenhancer描绘已标识ZNF395作为肾透明细胞癌特异性和VHL调节的主调节器，其耗尽导致近乎完全消除肿瘤的体外和体内。甚高频丢失主要是通过启动子来促进增强子/超增强子的解除调控，并在ccRCC标志基因附近获得活性增强子标记（H3K27ac，H3K4me1）。从机理上讲，VHL丢失可稳定增强子处的HIF2α–HIF1β异二聚体结合，随后募集组蛋白乙酰转移酶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，通过调节表观基因组格局和癌症基因表达，亚型特异性驱动子突变（例如VHL）可以在ccRCC中传播独特的致病依赖性。

意义： ccRCC的全面表观基因组学分析建立了由体细胞改变的顺式调控元件的纲要，发现了包括ccRCC主调控器ZNF395在内的新的潜在靶标。VHL的丢失（ccRCC签名事件）会导致普遍的增强子功能异常，与以增强子为中心的HIF2α结合并在先前存在的谱系特异性启动子-增强子复合体中募集组蛋白乙酰转移酶p300。巨蟹座Discov; 7（11）；1284–305。©2017 AACR。

参见Ricketts和Linehan，p。的相关评论。1221。

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