Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: Association with poor prognosis in head and neck cancer
Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: Association with poor prognosis in head and neck cancer
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DOI：
10.1002/hed.23663
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发表时间：
2015-05-01
影响因子：
2.9
通讯作者：
Lam, Wan L.
中科院分区：
文献类型：
--
作者：
Martinez, Victor D.;Vucic, Emily A.;Lam, Wan L.
研究背景NRF 2通路具有多种促肿瘤发生功能，在头颈部鳞状细胞癌（HNSCC）中NRF 2水平升高。KEAP 1/CUL 3/RBX 1 E3-泛素连接酶复合物是NRF 2的负调节因子。在这项研究中，我们调查了机制，破坏个别复杂的components.MethodsClinical和基因组图谱为302例HNSCC患者从癌症基因组图谱。单个组分的表观/遗传改变的组合模式显示频繁的复杂破坏。基因集富集分析进行表达数据，以确定受影响的pathways.ResultsDNA丢失是改变所有组成基因的主要机制，而超甲基化在很大程度上只影响KEAP 1。综合分析显示，64%的HNSCC患者的这种蛋白复合物被破坏。一致地，NRF 2相关基因标签在HNSCC中富集。生存显着减少患者中的一个或多个中断component.ConclusionThe KEAP 1/CUL 3/RBX 1 E3-泛素连接酶复合物是经常中断HNSCC的多种机制。基于NRF 2的遗传学将受益于组分基因的综合分析。(c)2014 Wiley Periodicals，Inc. Head Neck 37：727-734，2015
BackgroundThe NRF2 pathway has multiple pro-tumorigenic functions, and Nrf2 levels are increased in head and neck squamous cell carcinoma (HNSCC). The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a negative regulator of NRF2. In this study, we investigated mechanisms of disruption of individual complex components.MethodsClinical and genomic profiles for 302 patients with HNSCC were obtained from The Cancer Genome Atlas. Combined pattern of epi/genetic alterations for individual components revealed frequent of complex disruption. Gene-set enrichment analysis was performed on expression data to identify affected pathways.ResultsDNA loss is the main mechanism of alteration for all component genes, whereas hypermethylation largely affects only KEAP1. Combined analysis revealed that 64% of patients with HNSCC have disruption in this protein complex. Concordantly, NRF2-associated gene signature is enriched in HNSCC. Survival was significantly diminished among patients with one or more disrupted components.ConclusionThe KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is frequently disrupted in HNSCC by multiple mechanisms. NRF2-based prognostics will benefit from integrated analysis of component genes. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 727-734, 2015