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A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration

The non-receptor tyrosine kinase SRC is overexpressed and/or hyperactivated in various human cancers, and facilitates cancer progression by promoting invasion and metastasis. However, the mechanisms underlying SRC upregulation are poorly understood. In this study, we demonstrate that transforming gr...

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Autores principales: Noshita, Soshi, Kubo, Yuki, Kajiwara, Kentaro, Okuzaki, Daisuke, Nada, Shigeyuki, Okada, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445741/
https://www.ncbi.nlm.nih.gov/pubmed/37439249
http://dx.doi.org/10.1242/jcs.261001
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author Noshita, Soshi
Kubo, Yuki
Kajiwara, Kentaro
Okuzaki, Daisuke
Nada, Shigeyuki
Okada, Masato
author_facet Noshita, Soshi
Kubo, Yuki
Kajiwara, Kentaro
Okuzaki, Daisuke
Nada, Shigeyuki
Okada, Masato
author_sort Noshita, Soshi
collection PubMed
description The non-receptor tyrosine kinase SRC is overexpressed and/or hyperactivated in various human cancers, and facilitates cancer progression by promoting invasion and metastasis. However, the mechanisms underlying SRC upregulation are poorly understood. In this study, we demonstrate that transforming growth factor-β (TGF-β) induces SRC expression at the transcriptional level by activating an intragenic the SRC enhancer. In the human breast epithelial cell line MCF10A, TGF-β1 stimulation upregulated one of the SRC promotors, the 1A promoter, resulting in increased SRC mRNA and protein levels. Chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the SMAD complex is recruited to three enhancer regions ∼15 kb upstream and downstream of the SRC promoter, and one of them is capable of activating the SRC promoter in response to TGF-β. JUN, a member of the activator protein (AP)-1 family, localises to the enhancer and regulates TGF-β-induced SRC expression. Furthermore, TGF-β-induced SRC upregulation plays a crucial role in epithelial–mesenchymal transition (EMT)-associated cell migration by activating the SRC–focal adhesion kinase (FAK) circuit. Overall, these results suggest that TGF-β-induced SRC upregulation promotes cancer cell invasion and metastasis in a subset of human malignancies.
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spelling pubmed-104457412023-08-24 A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration Noshita, Soshi Kubo, Yuki Kajiwara, Kentaro Okuzaki, Daisuke Nada, Shigeyuki Okada, Masato J Cell Sci Research Article The non-receptor tyrosine kinase SRC is overexpressed and/or hyperactivated in various human cancers, and facilitates cancer progression by promoting invasion and metastasis. However, the mechanisms underlying SRC upregulation are poorly understood. In this study, we demonstrate that transforming growth factor-β (TGF-β) induces SRC expression at the transcriptional level by activating an intragenic the SRC enhancer. In the human breast epithelial cell line MCF10A, TGF-β1 stimulation upregulated one of the SRC promotors, the 1A promoter, resulting in increased SRC mRNA and protein levels. Chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the SMAD complex is recruited to three enhancer regions ∼15 kb upstream and downstream of the SRC promoter, and one of them is capable of activating the SRC promoter in response to TGF-β. JUN, a member of the activator protein (AP)-1 family, localises to the enhancer and regulates TGF-β-induced SRC expression. Furthermore, TGF-β-induced SRC upregulation plays a crucial role in epithelial–mesenchymal transition (EMT)-associated cell migration by activating the SRC–focal adhesion kinase (FAK) circuit. Overall, these results suggest that TGF-β-induced SRC upregulation promotes cancer cell invasion and metastasis in a subset of human malignancies. The Company of Biologists Ltd 2023-08-09 /pmc/articles/PMC10445741/ /pubmed/37439249 http://dx.doi.org/10.1242/jcs.261001 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Noshita, Soshi
Kubo, Yuki
Kajiwara, Kentaro
Okuzaki, Daisuke
Nada, Shigeyuki
Okada, Masato
A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title_full A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title_fullStr A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title_full_unstemmed A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title_short A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration
title_sort tgf-β-responsive enhancer regulates src expression and epithelial–mesenchymal transition-associated cell migration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445741/
https://www.ncbi.nlm.nih.gov/pubmed/37439249
http://dx.doi.org/10.1242/jcs.261001
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