25年前EVI1基因被發(fā)現(xiàn)以來，后續(xù)研究證實該轉(zhuǎn)錄因子在許多不同類型的癌癥包括乳腺癌,，前列腺癌和結(jié)腸癌,、白血病等中都存在。例如在美國,，NanoOncology公司已開始開發(fā)阻斷這種基因的藥物,。然而只有極少數(shù)的EVI1下游靶基因是已知的,。
近日，A*STAR研究所分子與細(xì)胞生物學(xué)教授Emilie Bard-Chapeau等人使用系統(tǒng)生物學(xué)的方法,，確定了EVI1控制的腫瘤相關(guān)基因,。這一發(fā)現(xiàn)可能導(dǎo)致出現(xiàn)新的治療藥物，以抗擊各種形式的癌癥,。
利用微陣列芯片測序和免疫檢測,，研究人員發(fā)現(xiàn)EVI1的兩種不同的鋅指域能激活靶基因，這些靶基因中有許多是參與細(xì)胞黏附,、增殖,、集落形成和腫瘤生長等方面的。
值得注意的是,，研究人員探究了EVI1和FOS之間的關(guān)聯(lián)性,，F(xiàn)OS是激活蛋白1（AP 1）轉(zhuǎn)錄因子的主要構(gòu)成成員之一。在細(xì)胞模型上的實驗表明EVI1和FOS相互作用共同調(diào)控許多腫瘤的標(biāo)志物,，晚期卵巢癌患者采取后續(xù)分析研究后發(fā)現(xiàn)EVI1和AP1也都富集表達(dá),。
研究人員表示：這項研究揭示了EVI1的調(diào)控機制，證實了EVI1是許多晚期癌癥的關(guān)鍵調(diào)控因子,。破壞EVI1和FOS之間的相互作用,，可能是一個能防止癌癥發(fā)展的非常有希望的治療手段。（生物谷：Bioon.com）
doi:10.1073/pnas.1119229109
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PMID:
Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors
Emilie A. Bard-Chapeaua, Justin Jeyakanib, Chung H. Kokc, Julius Mullera, Belinda Q. Chuaa, Jayantha Gunaratnea, Arsen Batagovd, et al.
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.
