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, Enzo Agostinelli, Beatrice Cardinali, Isabella Screpanti, Alberto Gulino, Gianluca Canettieri

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish
Article number3398
Pages (from-to)21-35
Number of pages15
JournalDevelopmental Cell
Volume35
Issue number1
DOIs
Publication statusPublished - Oct 12 2015

ASJC Scopus subject areas

  • Developmental Biology

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