4.8 Article

FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer

期刊

SCIENCE ADVANCES
卷 9, 期 33, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.adg7112

关键词

-

向作者/读者索取更多资源

Based on the study of FOXA1 O-beta-N-acetylglucosamine modification (O-GlcNAcylation), it was found that O-GlcNAcylation promotes breast cancer metastasis by regulating the transcription of multiple metastasis regulators. O-GlcNAcylation regulates the stability of FOXA1 and promotes its chromatin assembly, shaping the interactome of FOXA1 and triggering the recruitment of transcriptional repressor methyl-CpG binding protein 2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes, inhibiting breast cancer proliferation and metastasis. These findings establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and suggest that targeting O-GlcNAcylation could be a therapeutic strategy for metastatic 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 beta-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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据