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FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer
FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 p...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10438466/ https://www.ncbi.nlm.nih.gov/pubmed/37595040 http://dx.doi.org/10.1126/sciadv.adg7112 |
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author | Liu, Yajie Yu, Kairan Kong, Xiaotian Zhang, Keren Wang, Lingyan Zhang, Nana Chen, Qiushi Niu, Mingshan Li, Wenli Zhong, Xiaomin Wu, Sijin Zhang, Jianing Liu, Yubo |
author_facet | Liu, Yajie Yu, Kairan Kong, Xiaotian Zhang, Keren Wang, Lingyan Zhang, Nana Chen, Qiushi Niu, Mingshan Li, Wenli Zhong, Xiaomin Wu, Sijin Zhang, Jianing Liu, Yubo |
author_sort | Liu, Yajie |
collection | PubMed |
description | FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr(432), Ser(441), and Ser(443) regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer. |
format | Online Article Text |
id | pubmed-10438466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-104384662023-08-19 FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer Liu, Yajie Yu, Kairan Kong, Xiaotian Zhang, Keren Wang, Lingyan Zhang, Nana Chen, Qiushi Niu, Mingshan Li, Wenli Zhong, Xiaomin Wu, Sijin Zhang, Jianing Liu, Yubo Sci Adv Biomedicine and Life Sciences FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr(432), Ser(441), and Ser(443) regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer. American Association for the Advancement of Science 2023-08-18 /pmc/articles/PMC10438466/ /pubmed/37595040 http://dx.doi.org/10.1126/sciadv.adg7112 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Liu, Yajie Yu, Kairan Kong, Xiaotian Zhang, Keren Wang, Lingyan Zhang, Nana Chen, Qiushi Niu, Mingshan Li, Wenli Zhong, Xiaomin Wu, Sijin Zhang, Jianing Liu, Yubo FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title | FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title_full | FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title_fullStr | FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title_full_unstemmed | FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title_short | FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
title_sort | foxa1 o-glcnacylation–mediated transcriptional switch governs metastasis capacity in breast cancer |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10438466/ https://www.ncbi.nlm.nih.gov/pubmed/37595040 http://dx.doi.org/10.1126/sciadv.adg7112 |
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