PNAS：EVI1促进癌症发展和肿瘤浸润的机制

25年前EVI1基因被发现以来，后续研究证实该转录因子在许多不同类型的癌症包括乳腺癌，前列腺癌和结肠癌、白血病等中都存在。例如在美国，NanoOncology公司已开始开发阻断这种基因的药物。然而只有极少数的EVI1下游靶基因是已知的。

近日，A*STAR研究所分子与细胞生物学教授Emilie Bard-Chapeau等人使用系统生物学的方法，确定了EVI1控制的肿瘤相关基因。这一发现可能导致出现新的治疗药物，以抗击各种形式的癌症。

利用微阵列芯片测序和免疫检测，研究人员发现EVI1的两种不同的锌指域能激活靶基因，这些靶基因中有许多是参与细胞黏附、增殖、集落形成和肿瘤生长等方面的。

值得注意的是，研究人员探究了EVI1和FOS之间的关联性，FOS是激活蛋白1（AP 1）转录因子的主要构成成员之一。在细胞模型上的实验表明EVI1和FOS相互作用共同调控许多肿瘤的标志物，晚期卵巢癌患者采取后续分析研究后发现EVI1和AP1也都富集表达。

研究人员表示：这项研究揭示了EVI1的调控机制，证实了EVI1是许多晚期癌症的关键调控因子。破坏EVI1和FOS之间的相互作用，可能是一个能防止癌症发展的非常有希望的治疗手段。

doi:10.1073/pnas.1119229109
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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.