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EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis
Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcrip...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175245/ https://www.ncbi.nlm.nih.gov/pubmed/29873416 http://dx.doi.org/10.1002/mc.22849 |
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author | Sen, Nirmalya Cross, Allison M. Lorenzi, Philip L. Khan, Javed Gryder, Berkley E. Kim, Suntae Caplen, Natasha J. |
author_facet | Sen, Nirmalya Cross, Allison M. Lorenzi, Philip L. Khan, Javed Gryder, Berkley E. Kim, Suntae Caplen, Natasha J. |
author_sort | Sen, Nirmalya |
collection | PubMed |
description | Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS‐FLI1 positively regulates the expression of proteins required for serine‐glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS‐FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell‐based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS‐FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one‐carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine‐glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS‐FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low‐ and high‐risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS‐FLI1 reprograms the metabolism of EWS cells and that serine‐glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type. |
format | Online Article Text |
id | pubmed-6175245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61752452018-10-15 EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis Sen, Nirmalya Cross, Allison M. Lorenzi, Philip L. Khan, Javed Gryder, Berkley E. Kim, Suntae Caplen, Natasha J. Mol Carcinog Articles Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS‐FLI1 positively regulates the expression of proteins required for serine‐glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS‐FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell‐based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS‐FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one‐carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine‐glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS‐FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low‐ and high‐risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS‐FLI1 reprograms the metabolism of EWS cells and that serine‐glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type. John Wiley and Sons Inc. 2018-06-19 2018-10 /pmc/articles/PMC6175245/ /pubmed/29873416 http://dx.doi.org/10.1002/mc.22849 Text en © 2018 The Authors. Molecular Carcinogenesis Published by WileyPeriodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Sen, Nirmalya Cross, Allison M. Lorenzi, Philip L. Khan, Javed Gryder, Berkley E. Kim, Suntae Caplen, Natasha J. EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title | EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title_full | EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title_fullStr | EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title_full_unstemmed | EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title_short | EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
title_sort | ews‐fli1 reprograms the metabolism of ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175245/ https://www.ncbi.nlm.nih.gov/pubmed/29873416 http://dx.doi.org/10.1002/mc.22849 |
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