Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma.
Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma.
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二价因子DLX5的激活与主调控因子TP63协同促进鳞状细胞癌
DOI：
10.1093/nar/gkab679
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发表时间：
2021-09-20
影响因子：
14.9
通讯作者：
Yin D
中科院分区：
文献类型：
--
作者：
Huang Y;Yang Q;Zheng Y;Lin L;Xu X;Xu XE;Silva TC;Hazawa M;Peng L;Cao H;Ding Y;Lu D;Berman BP;Xu LY;Li EM;Yin D
摘要为了系统地重建鳞状细胞癌（SCC）中过度活跃的转录因子（TF）依赖的转录网络，将计算方法（ELMER）应用于1293例泛SCC患者样本，并确定了44个过度活跃的SCC TF。作为最佳候选者，DLX 5在癌症中表现出其二价启动子的显著分叉重构。具体而言，DLX 5在正常组织中保持二价状态;其启动子是高甲基化的，导致食管腺癌（EAC）中DLX 5转录沉默。与此形成鲜明对比的是，DLX 5启动子获得活性组蛋白标记，并在ESCC中被转录激活，这是由SOX 2直接介导的。在功能上，DLX 5的沉默在体外和体内均显著抑制SCC活力。从机制上讲，DLX 5与TP 63在调节T2000增强子和启动子方面合作，这些增强子和启动子集中在激活癌症促进途径上。总之，我们的数据建立了一个新的和强大的SCC促进因子，并阐明了一个新的表观基因组机制-分叉染色质重新配置-在癌症的发展。
Abstract To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.
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影响因子：
64.8
作者：
Cancer Genome Atlas Research Network;Analysis Working Group: Asan University;BC Cancer Agency;Brigham and Women’s Hospital;Broad Institute;Brown University;Case Western Reserve University;Dana-Farber Cancer Institute;Duke University;Greater Poland Cancer Centre;Harvard Medical School;Institute for Systems Biology;KU Leuven;Mayo Clinic;Memorial Sloan Kettering Cancer Center;National Cancer Institute;Nationwide Children’s Hospital;Stanford University;University of Alabama;University of Michigan;University of North Carolina;University of Pittsburgh;University of Rochester;University of Southern California;University of Texas MD Anderson Cancer Center;University of Washington;Van Andel Research Institute;Vanderbilt University;Washington University;Genome Sequencing Center: Broad Institute;Washington University in St. Louis;Genome Characterization Centers: BC Cancer Agency;Broad Institute;Harvard Medical School;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of North Carolina;University of Southern California Epigenome Center;University of Texas MD Anderson Cancer Center;Van Andel Research Institute;Genome Data Analysis Centers: Broad Institute;Brown University:;Harvard Medical School;Institute for Systems Biology;Memorial Sloan Kettering Cancer Center;University of California Santa Cruz;University of Texas MD Anderson Cancer Center;Biospecimen Core Resource: International Genomics Consortium;Research Institute at Nationwide Children’s Hospital;Tissue Source Sites: Analytic Biologic Services;Asan Medical Center;Asterand Bioscience;Barretos Cancer Hospital;BioreclamationIVT;Botkin Municipal Clinic;Chonnam National University Medical School;Christiana Care Health System;Cureline;Duke University;Emory University;Erasmus University;Indiana University School of Medicine;Institute of Oncology of Moldova;International Genomics Consortium;Invidumed;Israelitisches Krankenhaus Hamburg;Keimyung University School of Medicine;Memorial Sloan Kettering Cancer Center;National Cancer Center Goyang;Ontario Tumour Bank;Peter MacCallum Cancer Centre;Pusan National University Medical School;Ribeirão Preto Medical School;St. Joseph’s Hospital &Medical Center;St. Petersburg Academic University;Tayside Tissue Bank;University of Dundee;University of Kansas Medical Center;University of Michigan;University of North Carolina at Chapel Hill;University of Pittsburgh School of Medicine;University of Texas MD Anderson Cancer Center;Disease Working Group: Duke University;Memorial Sloan Kettering Cancer Center;National Cancer Institute;University of Texas MD Anderson Cancer Center;Yonsei University College of Medicine;Data Coordination Center: CSRA Inc.;Project Team: National Institutes of Health
通讯作者：
Project Team: National Institutes of Health
影响因子：
64.8
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
15.9
作者：
Brooks, Yang Sui;Ostano, Paola;Dotto, G. Paolo
通讯作者：
Dotto, G. Paolo
影响因子：
30.8
作者：
Horike, S;Cai, ST;Kohwi-Shigematsu, T
通讯作者：
Kohwi-Shigematsu, T
影响因子：
7
作者：
Easwaran, Hariharan;Johnstone, Sarah E.;Baylin, Stephen B.
通讯作者：
Baylin, Stephen B.