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

Oncogene volume 30, pages 410–422 (2011)Cite this article

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A Corrigendum to this article was published on 27 January 2011

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 Shh→E2F1→FASN 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.

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Acknowledgements

We thank Dr Michael J Klein and the Pathology and Laboratory Medicine group at the Hospital for Special Surgery and MSKCC microcyteometry facility. We also thank Lori A Mainwaring, Cedric Dray, Cemille Guldal, Elisa DeStanchina and Fajun Yang for helpful discussions. These studies were funded by the Lung Cancer Center and the division of thoracic surgery at Weill Cornell Medical College (ZN), the NIH (NINDS R01NS061070) (AMK) and the Memorial Sloan–Kettering Brain Tumor Center (BB).

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  1. Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY, USA

    B Bhatia & A M Kenney

  2. Department of Cancer Biology and Genetics, Memorial Sloan–Kettering Cancer Center, New York, NY, USA

    M Hsieh & Z Nahlé

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  1. B Bhatia
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Bhatia, B., Hsieh, M., Kenney, A. et al. Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma. Oncogene 30, 410–422 (2011). https://doi.org/10.1038/onc.2010.454

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