Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors
Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors
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DOI：
10.1073/pnas.1119229109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Copeland, Neal G.
中科院分区：
文献类型：
--
作者：
Bard-Chapeau, Emilie A.;Jeyakani, Justin;Copeland, Neal G.
生态亲和性病毒整合位点1 （Ecotropic viral integration site 1, EVI1）是一种致癌双结构域锌指转录因子，在造血干细胞更新调控中起重要作用，其在髓性白血病和上皮性癌症中的过表达与患者生存率低有关。尽管EVI1于1988年被发现，并在各种类型的癌症中作为显性癌基因出现，但已知的EVI1靶基因很少。这种知识的缺乏阻碍了对EVI1如何导致癌症的确切理解。通过对人卵巢癌细胞的ChIP-Seq和微阵列研究，我们发现EVI1的两个锌指结构域独立结合DNA并调节不同的靶基因。引人注目的是，EVI1靶基因的富集部分是癌症基因或与癌症相关的基因。我们还发现，超过25%的EVI1占据的基因含有连接的EVI1和激活蛋白（AP）1 DNA结合位点，这一发现为EVI1和AP1家族成员FOS在调节细胞粘附、增殖和集落形成方面的协同相互作用提供了证据。EVI1/AP1双靶基因数量的增加在晚期卵巢癌中也存在差异调控，进一步证实了EVI1与FOS之间功能合作的重要性。总的来说，我们的数据表明，EVI1是一种多用途转录因子，在侵袭性肿瘤中与FOS协同作用。
Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors.