TY - JOUR
T1 - Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth
AU - D'Amico, Davide
AU - Antonucci, Laura
AU - Di Magno, Laura
AU - Coni, Sonia
AU - Sdruscia, Giulia
AU - Macone, Alberto
AU - Miele, Evelina
AU - Infante, Paola
AU - Di Marcotullio, Lucia
AU - De Smaele, Enrico
AU - Ferretti, Elisabetta
AU - Ciapponi, Laura
AU - Giangaspero, Felice
AU - Yates, John R.
AU - Agostinelli, Enzo
AU - Cardinali, Beatrice
AU - Screpanti, Isabella
AU - Gulino, Alberto
AU - Canettieri, Gianluca
PY - 2015/10/12
Y1 - 2015/10/12
N2 - 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. D'Amico, Antonucci, and colleagues identify a non-canonical Hedgehog-dependent pathway that controls polyamine metabolism. The pathway involves the energy sensor AMPK and the translational regulator CNBP and is essential for Hh-dependent proliferation of medulloblastoma cells. The authors show that targeting this pathway efficiently restrains tumor growth.
AB - 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. D'Amico, Antonucci, and colleagues identify a non-canonical Hedgehog-dependent pathway that controls polyamine metabolism. The pathway involves the energy sensor AMPK and the translational regulator CNBP and is essential for Hh-dependent proliferation of medulloblastoma cells. The authors show that targeting this pathway efficiently restrains tumor growth.
UR - http://www.scopus.com/inward/record.url?scp=84945252145&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945252145&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2015.09.008
DO - 10.1016/j.devcel.2015.09.008
M3 - Article
AN - SCOPUS:84945252145
VL - 35
SP - 21
EP - 35
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 1
M1 - 3398
ER -