Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma Journal Article

Authors: Bhatia, B.; Hsieh, M.; Kenney, A. M.; Nahlé, Z.
Article Title: Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma
Abstract: Deregulation of the Rb/E2F tumor suppressor complex and aberrantion of Sonic hedgehog (Shh) signaling are documented across the spectrum of human malignancies. Exaggerated de novo lipid synthesis is also found in certain highly proliferative, aggressive tumors. Here, we show that in Shh-driven medulloblastomas, Rb is inactivated and E2F1 is upregulated, promoting lipogenesis. Extensive lipid accumulation and elevated levels of the lipogenic enzyme fatty acid synthase (FASN) mark those tumors. In primary cerebellar granule neuron precursors (CGNPs), proposed Shh-associated medulloblastoma cells-of-origin, Shh signaling triggers E2F1 and FASN expression, whereas suppressing fatty acid oxidation (FAO), in a smoothened-dependent manner. In the developing cerebellum, E2F1 and FASN co-localize in proliferating CGNPs. in vivo and in vitro, E2F1 is required for FASN expression and CGNP proliferation, and E2F1 knockdown impairs Shh-mediated FAO inhibition. Pharmacological blockade of Rb inactivation and/or lipogenesis inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals In vivo. These findings identify a novel mechanism through which Shh signaling links cell cycle progression to lipid synthesis, through E2F1-dependent regulation of lipogenic enzymes. These findings pertinent to the etiology of tumor metabolism also underscore the key role of the ShhE2F1FASN axis in regulating de novo lipid synthesis in cancers, and as such its value as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors. © 2011 Macmillan Publishers Limited All rights reserved.
Keywords: metabolism; medulloblastoma; sonic hedgehog; lipogenesis; rb; e2f1
Journal Title: Oncogene
Volume: 30
Issue: 4
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2011-01-27
Start Page: 410
End Page: 422
Language: English
DOI: 10.1038/onc.2010.454
PROVIDER: scopus
PMCID: PMC3072890
PUBMED: 20890301
Notes: Erratum issued, see DOI: 10.1038/onc.2010.454 -- "Export Date: 4 March 2011" - "CODEN: ONCNE" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Bipin Bhatia
    13 Bhatia
  2. Anna Marie Kenney
    34 Kenney