title: Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites.
abstract: PBX1 is a TALE homeodomain transcription factor involved in organogenesis and tumorigenesis. Although it has been shown that ovarian, breast, and melanoma cancer cells depend on PBX1 for cell growth and survival, the molecular mechanism of how PBX1 promotes tumorigenesis remains unclear. Here, we applied an integrated approach by overlapping PBX1 ChIP-chip targets with the PBX1-regulated transcriptome in ovarian cancer cells to identify genes whose transcription was directly regulated by PBX1. We further determined if PBX1 target genes identified in ovarian cancer cells were co-overexpressed with PBX1 in carcinoma tissues. By analyzing TCGA gene expression microarray datasets from ovarian serous carcinomas, we found co-upregulation of PBX1 and a significant number of its direct target genes. Among the PBX1 target genes, a homeodomain protein MEOX1 whose DNA binding motif was enriched in PBX1-immunoprecipicated DNA sequences was selected for functional analysis. We demonstrated that MEOX1 protein interacts with PBX1 protein and inhibition of MEOX1 yields a similar growth inhibitory phenotype as PBX1 suppression. Furthermore, ectopically expressed MEOX1 functionally rescued the PBX1-withdrawn effect, suggesting MEOX1 mediates the cellular growth signal of PBX1. These results demonstrate that MEOX1 is a critical target gene and cofactor of PBX1 in ovarian cancers.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Thiaville
authors.forename: Alexander
authors.initials: A
authors.lastname: Stoeck
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Ren-Chin
authors.initials: RC
authors.lastname: Wu
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.forename: Jessica
authors.initials: J
authors.lastname: Oidtman
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
mesh_terms: D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018398:Homeodomain Proteins; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C525671:MEOX1 protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human