Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is en...

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Autores principales: Chen, Wei-Ching, To, Minh D., Westcott, Peter M. K., Delrosario, Reyno, Kim, Il-Jin, Philips, Mark, Tran, Quan, Bollam, Saumya R., Goodarzi, Hani, Bayani, Nora, Mirzoeva, Olga, Balmain, Allan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277813/
https://www.ncbi.nlm.nih.gov/pubmed/34257283
http://dx.doi.org/10.1038/s41467-021-24498-7
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author Chen, Wei-Ching
To, Minh D.
Westcott, Peter M. K.
Delrosario, Reyno
Kim, Il-Jin
Philips, Mark
Tran, Quan
Bollam, Saumya R.
Goodarzi, Hani
Bayani, Nora
Mirzoeva, Olga
Balmain, Allan
author_facet Chen, Wei-Ching
To, Minh D.
Westcott, Peter M. K.
Delrosario, Reyno
Kim, Il-Jin
Philips, Mark
Tran, Quan
Bollam, Saumya R.
Goodarzi, Hani
Bayani, Nora
Mirzoeva, Olga
Balmain, Allan
author_sort Chen, Wei-Ching
collection PubMed
description The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.
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spelling pubmed-82778132021-07-20 Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells Chen, Wei-Ching To, Minh D. Westcott, Peter M. K. Delrosario, Reyno Kim, Il-Jin Philips, Mark Tran, Quan Bollam, Saumya R. Goodarzi, Hani Bayani, Nora Mirzoeva, Olga Balmain, Allan Nat Commun Article The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics. Nature Publishing Group UK 2021-07-13 /pmc/articles/PMC8277813/ /pubmed/34257283 http://dx.doi.org/10.1038/s41467-021-24498-7 Text en © The Author(s) 2021 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 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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chen, Wei-Ching
To, Minh D.
Westcott, Peter M. K.
Delrosario, Reyno
Kim, Il-Jin
Philips, Mark
Tran, Quan
Bollam, Saumya R.
Goodarzi, Hani
Bayani, Nora
Mirzoeva, Olga
Balmain, Allan
Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title_full Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title_fullStr Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title_full_unstemmed Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title_short Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
title_sort targeting kras4a splicing through the rbm39/dcaf15 pathway inhibits cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277813/
https://www.ncbi.nlm.nih.gov/pubmed/34257283
http://dx.doi.org/10.1038/s41467-021-24498-7
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