title: Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.
abstract: Developmental Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs), and its aberrant activation is a leading cause of medulloblastoma. We show here that Hedgehog promotes polyamine biosynthesis in GCPs by engaging a non-canonical axis leading to the translation of ornithine decarboxylase (ODC). This process is governed by AMPK, which phosphorylates threonine 173 of the zinc finger protein CNBP in response to Hedgehog activation. Phosphorylated CNBP increases its association with Sufu, followed by CNBP stabilization, ODC translation, and polyamine biosynthesis. Notably, CNBP, ODC, and polyamines are elevated in Hedgehog-dependent medulloblastoma, and genetic or pharmacological inhibition of this axis efficiently blocks Hedgehog-dependent proliferation of medulloblastoma cells in vitro and in vivo. Together, these data illustrate an auxiliary mechanism of metabolic control by a morphogenic pathway with relevant implications in development and cancer.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: D'Amico
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Antonucci
authors.affiliation: Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Magno
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Coni
authors.affiliation: Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sdruscia
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Macone
authors.affiliation: Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.affiliation: Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: Department of Biology and Biotechnologies, Sapienza University of Rome, Rome 00185, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ciapponi
authors.affiliation: Department of Radiological, Oncological, and Pathological Science, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Agostinelli
authors.affiliation: Cellular Biology and Neurobiology Institute, National Research Council, Monterotondo 00016, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Cardinali
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy. Electronic address: gianluca.canettieri@uniroma1.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011073:Polyamines / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: C433227:CNBP protein, human; D053823:Hedgehog Proteins; D011073:Polyamines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D055372:AMP-Activated Protein Kinases; D009955:Ornithine Decarboxylase