Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
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
_version_ 1785092798565842944
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
work_keys_str_mv AT liuyajie foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT yukairan foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT kongxiaotian foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT zhangkeren foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT wanglingyan foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT zhangnana foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT chenqiushi foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT niumingshan foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT liwenli foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT zhongxiaomin foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT wusijin foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT zhangjianing foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer
AT liuyubo foxa1oglcnacylationmediatedtranscriptionalswitchgovernsmetastasiscapacityinbreastcancer