title: Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells.
abstract: The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.
authors.affiliation: Science For Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden;
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akhtar Ali
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 85 Uppsala, Sweden; Department of Animal Production, Ain Shams University, Shoubra El-Kheima, 11241 Cairo, Egypt;
authors.forename: Shady
authors.initials: S
authors.lastname: Younis
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden;
authors.forename: Ola
authors.initials: O
authors.lastname: Wallerman
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 85 Uppsala, Sweden;
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 85 Uppsala, Sweden; Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden; Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843 leif.andersson@imbim.uu.se.
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Science For Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden;
authors.forename: Tobias
authors.initials: T
authors.lastname: Sjöblom
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D059467:Transcriptome
chemical_list: D012097:Repressor Proteins; D014157:Transcription Factors; C000602570:ZBED6 protein, human
keywords: IGF2; PI3K pathway; ZBED6; colorectal cancer