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

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 medul...

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Autores principales: Bhatia, Bobby, Hsieh, Michael, Kenney, Anna Marie, Nahlé, Zaher
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072890/
https://www.ncbi.nlm.nih.gov/pubmed/20890301
http://dx.doi.org/10.1038/onc.2010.454
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author Bhatia, Bobby
Hsieh, Michael
Kenney, Anna Marie
Nahlé, Zaher
author_facet Bhatia, Bobby
Hsieh, Michael
Kenney, Anna Marie
Nahlé, Zaher
author_sort Bhatia, Bobby
collection PubMed
description 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 up-regulated, promoting lipogenesis. Extensive lipid accumulation and elevated levels of the lipogenic enzyme 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 while 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. Pharmacologic 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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spelling pubmed-30728902011-07-27 Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma Bhatia, Bobby Hsieh, Michael Kenney, Anna Marie Nahlé, Zaher Oncogene Article 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 up-regulated, promoting lipogenesis. Extensive lipid accumulation and elevated levels of the lipogenic enzyme 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 while 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. Pharmacologic 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. 2010-10-04 2011-01-27 /pmc/articles/PMC3072890/ /pubmed/20890301 http://dx.doi.org/10.1038/onc.2010.454 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Bhatia, Bobby
Hsieh, Michael
Kenney, Anna Marie
Nahlé, Zaher
Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title_full Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title_fullStr Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title_full_unstemmed Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title_short Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and Medulloblastoma
title_sort mitogenic sonic hedgehog signaling drives e2f1-dependent lipogenesis in progenitor cells and medulloblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072890/
https://www.ncbi.nlm.nih.gov/pubmed/20890301
http://dx.doi.org/10.1038/onc.2010.454
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