title: Zfx facilitates tumorigenesis caused by activation of the Hedgehog pathway.
abstract: The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies.
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Palmer
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Galan-Caridad
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Weisberg
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Liang
authors.initials: L
authors.lastname: Lei
authors.affiliation: Division of Pediatric Hematology, Columbia University Medical Center, New York, New York.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Esquilin
authors.affiliation: Departments of Pathology, Neurology and Neuroscience, and Project A.L.S./Laboratory for Stem Cell Research, Columbia University Medical Center, New York, New York.
authors.forename: Gist F
authors.initials: GF
authors.lastname: Croft
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Brandon
authors.initials: B
authors.lastname: Wainwright
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. Department of Dermatology, Columbia University Medical Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Owens
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York. bvr2101@columbia.edu.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C062076:zinc finger protein, X-linked; C489967:UBE2J1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C551544:DIS3L protein, human; D012260:Ribonucleases