Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma
| Autor: | Anna Marie Kenney, Michael Hsieh, Zaher Nahlé, Bobby Bhatia |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
cerebellum Blotting Western Mice Transgenic Biology medulloblastoma medicine.disease_cause Article Mice sonic hedgehog 03 medical and health sciences 0302 clinical medicine Neural Stem Cells Genetics medicine Animals Immunoprecipitation cancer Hedgehog Proteins Sonic hedgehog Cerebellar Neoplasms Rb E2F Molecular Biology lipogenesis 030304 developmental biology Medulloblastoma 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Lipid metabolism medicine.disease Immunohistochemistry Hedgehog signaling pathway Disease Models Animal Fatty acid synthase E2F1 030220 oncology & carcinogenesis Lipogenesis biology.protein Cancer research cell cycle Fatty Acid Synthases biological phenomena cell phenomena and immunity Carcinogenesis metabolism E2F1 Transcription Factor Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2010.454 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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