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Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which ident...

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Autores principales: El‐Naggar, Amal M, Somasekharan, Syam Prakash, Wang, Yemin, Cheng, Hongwei, Negri, Gian Luca, Pan, Melvin, Wang, Xue Qi, Delaidelli, Alberto, Rafn, Bo, Cran, Jordan, Zhang, Fan, Zhang, Haifeng, Colborne, Shane, Gleave, Martin, Mandinova, Anna, Kedersha, Nancy, Hughes, Christopher S, Surdez, Didier, Delattre, Olivier, Wang, Yuzhuo, Huntsman, David G, Morin, Gregg B, Sorensen, Poul H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893361/
https://www.ncbi.nlm.nih.gov/pubmed/31668005
http://dx.doi.org/10.15252/embr.201948375
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author El‐Naggar, Amal M
Somasekharan, Syam Prakash
Wang, Yemin
Cheng, Hongwei
Negri, Gian Luca
Pan, Melvin
Wang, Xue Qi
Delaidelli, Alberto
Rafn, Bo
Cran, Jordan
Zhang, Fan
Zhang, Haifeng
Colborne, Shane
Gleave, Martin
Mandinova, Anna
Kedersha, Nancy
Hughes, Christopher S
Surdez, Didier
Delattre, Olivier
Wang, Yuzhuo
Huntsman, David G
Morin, Gregg B
Sorensen, Poul H
author_facet El‐Naggar, Amal M
Somasekharan, Syam Prakash
Wang, Yemin
Cheng, Hongwei
Negri, Gian Luca
Pan, Melvin
Wang, Xue Qi
Delaidelli, Alberto
Rafn, Bo
Cran, Jordan
Zhang, Fan
Zhang, Haifeng
Colborne, Shane
Gleave, Martin
Mandinova, Anna
Kedersha, Nancy
Hughes, Christopher S
Surdez, Didier
Delattre, Olivier
Wang, Yuzhuo
Huntsman, David G
Morin, Gregg B
Sorensen, Poul H
author_sort El‐Naggar, Amal M
collection PubMed
description Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS‐275 inhibits YB‐1 deacetylation, decreasing its binding to 5′‐UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS‐275 promotes rapid acetylation of the YB‐1 RNA‐binding protein at lysine‐81, blocking binding and translational activation of NFE2L2, as well as known YB‐1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS‐275 dramatically reduces sarcoma metastasis in vivo, but an MS‐275‐resistant YB‐1K81‐to‐alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS‐275‐treated mice. These studies describe a novel function for MS‐275 through enhanced YB‐1 acetylation, thus inhibiting YB‐1 translational control of key cytoprotective factors and its pro‐metastatic activity.
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spelling pubmed-68933612019-12-16 Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis El‐Naggar, Amal M Somasekharan, Syam Prakash Wang, Yemin Cheng, Hongwei Negri, Gian Luca Pan, Melvin Wang, Xue Qi Delaidelli, Alberto Rafn, Bo Cran, Jordan Zhang, Fan Zhang, Haifeng Colborne, Shane Gleave, Martin Mandinova, Anna Kedersha, Nancy Hughes, Christopher S Surdez, Didier Delattre, Olivier Wang, Yuzhuo Huntsman, David G Morin, Gregg B Sorensen, Poul H EMBO Rep Articles Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS‐275 inhibits YB‐1 deacetylation, decreasing its binding to 5′‐UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS‐275 promotes rapid acetylation of the YB‐1 RNA‐binding protein at lysine‐81, blocking binding and translational activation of NFE2L2, as well as known YB‐1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS‐275 dramatically reduces sarcoma metastasis in vivo, but an MS‐275‐resistant YB‐1K81‐to‐alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS‐275‐treated mice. These studies describe a novel function for MS‐275 through enhanced YB‐1 acetylation, thus inhibiting YB‐1 translational control of key cytoprotective factors and its pro‐metastatic activity. John Wiley and Sons Inc. 2019-10-31 2019-12-05 /pmc/articles/PMC6893361/ /pubmed/31668005 http://dx.doi.org/10.15252/embr.201948375 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
El‐Naggar, Amal M
Somasekharan, Syam Prakash
Wang, Yemin
Cheng, Hongwei
Negri, Gian Luca
Pan, Melvin
Wang, Xue Qi
Delaidelli, Alberto
Rafn, Bo
Cran, Jordan
Zhang, Fan
Zhang, Haifeng
Colborne, Shane
Gleave, Martin
Mandinova, Anna
Kedersha, Nancy
Hughes, Christopher S
Surdez, Didier
Delattre, Olivier
Wang, Yuzhuo
Huntsman, David G
Morin, Gregg B
Sorensen, Poul H
Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title_full Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title_fullStr Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title_full_unstemmed Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title_short Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
title_sort class i hdac inhibitors enhance yb‐1 acetylation and oxidative stress to block sarcoma metastasis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893361/
https://www.ncbi.nlm.nih.gov/pubmed/31668005
http://dx.doi.org/10.15252/embr.201948375
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