Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors.
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.
Institute of Molecular and Cell Biology,  Singapore 138673.
Emilie A
EA
Bard-Chapeau
Justin
J
Jeyakani
Chung H
CH
Kok
Julius
J
Muller
Belinda Q
BQ
Chua
Jayantha
J
Gunaratne
Arsen
A
Batagov
Piroon
P
Jenjaroenpun
Vladimir A
VA
Kuznetsov
Chia-Lin
CL
Wei
Richard J
RJ
D'Andrea
Guillaume
G
Bourque
Nancy A
NA
Jenkins
Neal G
NG
Copeland
D001665:Binding Sites; D002448:Cell Adhesion; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D004247:DNA