Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth

Davide D'Amico; Laura Antonucci; Laura Di Magno; Sonia Coni; Giulia Sdruscia; Alberto Macone; Evelina Miele; Paola Infante; Lucia Di Marcotullio; Enrico De Smaele; Elisabetta Ferretti; Laura Ciapponi; Felice Giangaspero; John R Yates 3rd; Enzo Agostinelli; Beatrice Cardinali; Isabella Screpanti; Alberto Gulino; Gianluca Canettieri

doi:10.1016/j.devcel.2015.09.008

Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth

Dev Cell. 2015 Oct 12;35(1):21-35. doi: 10.1016/j.devcel.2015.09.008.

Authors

Davide D'Amico¹, Laura Antonucci², Laura Di Magno³, Sonia Coni¹, Giulia Sdruscia³, Alberto Macone⁴, Evelina Miele³, Paola Infante³, Lucia Di Marcotullio⁵, Enrico De Smaele⁶, Elisabetta Ferretti⁶, Laura Ciapponi⁷, Felice Giangaspero⁸, John R Yates 3rd⁹, Enzo Agostinelli¹⁰, Beatrice Cardinali¹¹, Isabella Screpanti², Alberto Gulino¹², Gianluca Canettieri¹³

Affiliations

¹ Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
² Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
³ Center for Life Nanoscience@Sapienza, Italian Institute of Technology, Sapienza University of Rome, Rome 00161, Italy.
⁴ Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy.
⁵ 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.
⁶ Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
⁷ Department of Biology and Biotechnologies, Sapienza University of Rome, Rome 00185, Italy.
⁸ Department of Radiological, Oncological, and Pathological Science, Sapienza University of Rome, Rome 00161, Italy.
⁹ Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁰ Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
¹¹ Cellular Biology and Neurobiology Institute, National Research Council, Monterotondo 00016, Italy.
¹² 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.
¹³ Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy. Electronic address: gianluca.canettieri@uniroma1.it.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism*
Animals
Apoptosis
Blotting, Western
Cell Proliferation*
Cells, Cultured
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / metabolism
Cerebellar Neoplasms / pathology
Embryo, Mammalian / cytology
Embryo, Mammalian / metabolism
Female
Fibroblasts / cytology
Fibroblasts / metabolism
HEK293 Cells
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism*
Humans
Immunoprecipitation
Medulloblastoma / genetics
Medulloblastoma / metabolism
Medulloblastoma / pathology*
Mice
Mice, Nude
NIH 3T3 Cells
Neurons / cytology*
Neurons / metabolism
Ornithine Decarboxylase / genetics
Ornithine Decarboxylase / metabolism*
Phosphorylation
Polyamines / metabolism*
RNA, Messenger / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Real-Time Polymerase Chain Reaction
Repressor Proteins / genetics
Repressor Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Xenograft Model Antitumor Assays

Substances

CNBP protein, human
Hedgehog Proteins
Polyamines
RNA, Messenger
RNA-Binding Proteins
Repressor Proteins
SUFU protein, human
AMP-Activated Protein Kinases
Ornithine Decarboxylase

Abstract

Publication types

MeSH terms

Substances

Grants and funding