The PAX8 cistrome in epithelial ovarian cancer.
The PAX8 cistrome in epithelial ovarian cancer.
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DOI：
10.18632/oncotarget.22718
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发表时间：
2017-12-12
期刊：
影响因子：
--
通讯作者：
Gayther SA
中科院分区：
文献类型：
--
作者：
Adler EK;Corona RI;Lee JM;Rodriguez-Malave N;Mhawech-Fauceglia P;Sowter H;Hazelett DJ;Lawrenson K;Gayther SA
PAX8是一种谱系限制性转录因子，在上皮性卵巢癌（EOC）前体组织和主要的EOC组织型中表达。PAX8在原发性EOC中的频繁过表达表明该因子在肿瘤发生过程中作为癌基因起作用，然而，PAX8在EOC发展中的生物学作用尚不清楚。我们发现，在EOC模型中，稳定敲低PAX8可显著降低体外细胞增殖和锚定依赖性生长，并降低体内的致瘤性。染色质免疫沉淀，然后是下一代测序（ChIP-seq）和转录谱分析，用于创建PAX8结合基因和推定靶基因的全基因组图谱。PAX8结合位点显著富集于启动子区（p < 0.05）和超增强子区（p < 0.05）。MEME-ChIP分析显示，在JUND/B和ARNT/AHR基序中，PAX8结合位点富集了重叠增强子或增强子，而不是启动子。整合PAX8 ChIP-seq和基因表达数据，通过共享拓扑关联域内的关联确定PAX8靶基因。在两个EOC模型中，我们确定了62个基于PAX8在启动子中的结合的直接调控靶点和1330个假定的增强子调控靶点。SEPW1参与氧化还原，在两种细胞系模型中被鉴定为PAX8靶基因。虽然PAX8细胞群表现出高度的细胞类型特异性，但对PAX8靶基因和推定的辅助因子的分析确定了共同的分子靶点和伴侣作为EOC的候选治疗靶点。
PAX8 is a lineage-restricted transcription factor that is expressed in epithelial ovarian cancer (EOC) precursor tissues, and in the major EOC histotypes. Frequent overexpression of PAX8 in primary EOCs suggests this factor functions as an oncogene during tumorigenesis, however, the biological role of PAX8 in EOC development is poorly understood. We found that stable knockdown of PAX8 in EOC models significantly reduced cell proliferation and anchorage dependent growth in vitro, and attenuated tumorigenicity in vivo. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) and transcriptional profiling were used to create genome-wide maps of PAX8 binding and putative target genes. PAX8 binding sites were significantly enriched in promoter regions (p < 0.05) and superenhancers (p < 0.05). MEME-ChIP analysis revealed that PAX8 binding sites overlapping superenhancers or enhancers, but not promoters, were enriched for JUND/B and ARNT/AHR motifs. Integrating PAX8 ChIP-seq and gene expression data identified PAX8 target genes through their associations within shared topological association domains. Across two EOC models we identified 62 direct regulatory targets based on PAX8 binding in promoters and 1,330 putative enhancer regulatory targets. SEPW1, which is involved in oxidation-reduction, was identified as a PAX8 target gene in both cell line models. While the PAX8 cistrome exhibits a high degree of cell-type specificity, analyses of PAX8 target genes and putative cofactors identified common molecular targets and partners as candidate therapeutic targets for EOC.
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影响因子：
4.7
作者：
Elias KM;Labidi-Galy SI;Vitonis AF;Hornick JL;Doyle LA;Hirsch MS;Cramer DW;Drapkin R
通讯作者：
Drapkin R
DOI：
10.1056/nejmoa1110000
发表时间：
2012-01-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
通讯作者：
Cooney KA
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.6
作者：
Laury, Anna R.;Hornick, Jason L.;Hirsch, Michelle S.
通讯作者：
Hirsch, Michelle S.
DOI：
10.1073/pnas.96.6.3087
发表时间：
1999-03-16
影响因子：
11.1
作者：
Ilyas, M;Efstathiou, JA;Bodmer, WF
通讯作者：
Bodmer, WF