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The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism

The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic prop...

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Autores principales: Kaprio, Heidi, Siddiqui, Arafat, Saustila, Lotta, Heuser, Vanina D., Gardberg, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039922/
https://www.ncbi.nlm.nih.gov/pubmed/36966162
http://dx.doi.org/10.1038/s41598-023-31576-x
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author Kaprio, Heidi
Siddiqui, Arafat
Saustila, Lotta
Heuser, Vanina D.
Gardberg, Maria
author_facet Kaprio, Heidi
Siddiqui, Arafat
Saustila, Lotta
Heuser, Vanina D.
Gardberg, Maria
author_sort Kaprio, Heidi
collection PubMed
description The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic properties of the EWSR1::CREM protein have not previously been systematically characterized. In this study, we performed transcriptional profiling of the melanoma cell line CHL-1, with depletion of endogenous EWSR1::CREM protein using siRNA mediated knockdown. We found that the expression of 712 genes was altered (Log2 fold-change ≥ 2). We performed pathway analysis to identify EWSR1::CREM mediated pathways and cell studies to examine functional differences brought upon by the knockdown. Altered pathways involved cell cycle and proliferation, this was further validated by the cell studies where cell migration was affected as well. Among the target genes with the greatest downregulation, we discovered ODC1—a well-established oncogenic enzyme that can be pharmacologically inhibited and is essential for polyamine synthesis. We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies.
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spelling pubmed-100399222023-03-27 The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism Kaprio, Heidi Siddiqui, Arafat Saustila, Lotta Heuser, Vanina D. Gardberg, Maria Sci Rep Article The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic properties of the EWSR1::CREM protein have not previously been systematically characterized. In this study, we performed transcriptional profiling of the melanoma cell line CHL-1, with depletion of endogenous EWSR1::CREM protein using siRNA mediated knockdown. We found that the expression of 712 genes was altered (Log2 fold-change ≥ 2). We performed pathway analysis to identify EWSR1::CREM mediated pathways and cell studies to examine functional differences brought upon by the knockdown. Altered pathways involved cell cycle and proliferation, this was further validated by the cell studies where cell migration was affected as well. Among the target genes with the greatest downregulation, we discovered ODC1—a well-established oncogenic enzyme that can be pharmacologically inhibited and is essential for polyamine synthesis. We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies. Nature Publishing Group UK 2023-03-25 /pmc/articles/PMC10039922/ /pubmed/36966162 http://dx.doi.org/10.1038/s41598-023-31576-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kaprio, Heidi
Siddiqui, Arafat
Saustila, Lotta
Heuser, Vanina D.
Gardberg, Maria
The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title_full The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title_fullStr The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title_full_unstemmed The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title_short The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism
title_sort oncogenic properties of the ewsr1::crem fusion gene are associated with polyamine metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039922/
https://www.ncbi.nlm.nih.gov/pubmed/36966162
http://dx.doi.org/10.1038/s41598-023-31576-x
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