Editors' ChoiceCancer

Hedgehog stimulates polyamine biosynthesis

Sci. Signal.  20 Oct 2015:
Vol. 8, Issue 399, pp. ec299
DOI: 10.1126/scisignal.aad6468

Hedgehog (Hh) signaling stimulates proliferation of granule cell precursors (GCPs) in the developing cerebellum, and excessive Hh signaling in these cells causes medulloblastoma. In canonical Hh signaling, binding of Hh family ligands, such as Shh, to the receptor Patched (Ptch) relieves Ptch-mediated repression of the transmembrane protein Smoothened (Smo), thus stimulating cleavage of the transcription factor Gli into an activated form. Suppressor of fused (Sufu) limits Gli activity. D'Amico et al. found that application of Shh to isolated GCPs increased the abundance of polyamines and stimulated proliferation. Inhibiting ornithine decarboxylase (ODC), an enzyme required for polyamine biosynthesis, with difluoromethylornitine (DFMO) prevented Shh-induced proliferation of GCPs. Experiments in Ptch–/– and Sufu–/– MEFs suggested that Sufu stimulated polyamine biosynthesis by promoting the accumulation of ODC. Experiments in HEK293 and NIH3T3 cells showed that Sufu bound to and stabilized the CCHC-type nucleic acid binding protein (CNBP), a stimulator of ODC translation. In NIH3T3 cells, stimulation of Hh signaling with the Smo agonist SAG promoted the binding of CNBP to ODC transcripts and increased the abundance of ODC. This SAG-induced increase in ODC abundance required phosphorylation of CNBP by AMP-activated protein kinase (AMPK), which can be activated by Hh signaling through a Smo-dependent, Gli-independent mechanism. Compared with wild-type cerebellar cells, the abundance of Sufu, activated AMPK, CNBP, ODC, and polyamines was increased in medulloblastoma cells isolated from mice lacking Ptch in neural progenitor cells. Treating these primary murine medulloblastoma cells with DFMO or knocking down CNBP reduced proliferation and polyamine abundance. DFMO also inhibited the proliferation of TC-71 tumor cells, which are resistant to Smo inhibitors. CNBP and ODC abundance was increased in patient-derived samples of medullablastomas characterized by increased Shh signaling, suggesting that DMFO, which is already in clinical trials for treating neuroblastoma (see Zhao and Segal), may also be effective against medulloblastoma.

D. D’Amico, L. Antonucci, L. Di Magno, S. Coni, G. Sdruscia, A. Macone, E. Miele, P. Infante, L. Di Marcotullio, E. De Smaele, E. Ferretti, L. Ciapponi, F. Giangaspero, J. R. Yates III, E. Agostinelli, B. Cardinali, I. Screpanti, A. Gulino, G. Canettieri, Non-canonical Hedgehog/AMPK-mediated control of polyamine metabolism supports neuronal and medulloblastoma cell growth. Dev. Cell 35, 21–35 (2015). [PubMed]

X. Zhao, R. A. Segal, A polyamine twist on Hedgehog signaling. Dev. Cell 35, 1–2 (2015). [PubMed]