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Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation
Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypu...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729396/ https://www.ncbi.nlm.nih.gov/pubmed/33303756 http://dx.doi.org/10.1038/s41419-020-03174-6 |
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author | Coni, Sonia Serrao, Silvia Maria Yurtsever, Zuleyha Nihan Di Magno, Laura Bordone, Rosa Bertani, Camilla Licursi, Valerio Ianniello, Zaira Infante, Paola Moretti, Marta Petroni, Marialaura Guerrieri, Francesca Fatica, Alessandro Macone, Alberto De Smaele, Enrico Di Marcotullio, Lucia Giannini, Giuseppe Maroder, Marella Agostinelli, Enzo Canettieri, Gianluca |
author_facet | Coni, Sonia Serrao, Silvia Maria Yurtsever, Zuleyha Nihan Di Magno, Laura Bordone, Rosa Bertani, Camilla Licursi, Valerio Ianniello, Zaira Infante, Paola Moretti, Marta Petroni, Marialaura Guerrieri, Francesca Fatica, Alessandro Macone, Alberto De Smaele, Enrico Di Marcotullio, Lucia Giannini, Giuseppe Maroder, Marella Agostinelli, Enzo Canettieri, Gianluca |
author_sort | Coni, Sonia |
collection | PubMed |
description | Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APC(Min/+) mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy. |
format | Online Article Text |
id | pubmed-7729396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77293962020-12-17 Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation Coni, Sonia Serrao, Silvia Maria Yurtsever, Zuleyha Nihan Di Magno, Laura Bordone, Rosa Bertani, Camilla Licursi, Valerio Ianniello, Zaira Infante, Paola Moretti, Marta Petroni, Marialaura Guerrieri, Francesca Fatica, Alessandro Macone, Alberto De Smaele, Enrico Di Marcotullio, Lucia Giannini, Giuseppe Maroder, Marella Agostinelli, Enzo Canettieri, Gianluca Cell Death Dis Article Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APC(Min/+) mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy. Nature Publishing Group UK 2020-12-10 /pmc/articles/PMC7729396/ /pubmed/33303756 http://dx.doi.org/10.1038/s41419-020-03174-6 Text en © The Author(s) 2020 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Coni, Sonia Serrao, Silvia Maria Yurtsever, Zuleyha Nihan Di Magno, Laura Bordone, Rosa Bertani, Camilla Licursi, Valerio Ianniello, Zaira Infante, Paola Moretti, Marta Petroni, Marialaura Guerrieri, Francesca Fatica, Alessandro Macone, Alberto De Smaele, Enrico Di Marcotullio, Lucia Giannini, Giuseppe Maroder, Marella Agostinelli, Enzo Canettieri, Gianluca Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title | Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title_full | Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title_fullStr | Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title_full_unstemmed | Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title_short | Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation |
title_sort | blockade of eif5a hypusination limits colorectal cancer growth by inhibiting myc elongation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729396/ https://www.ncbi.nlm.nih.gov/pubmed/33303756 http://dx.doi.org/10.1038/s41419-020-03174-6 |
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