FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer.
FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer.
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DOI：
10.1126/sciadv.adg7112
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发表时间：
2023-08-18
期刊：
影响因子：
13.6
通讯作者：
Liu, Yubo
中科院分区：
文献类型：
--
作者：
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 是一种参与表观遗传重编程的转录因子，对于乳腺癌的进展至关重要。然而，FOXA1 实现其致癌功能的机制仍不清楚。在这里，我们证明 FOXA1 的 O-连接 β-N-乙酰氨基葡萄糖修饰（O-GlcNAcylation）通过协调众多转移调节因子的转录来促进乳腺癌转移。 Thr432、Ser441 和 Ser443 处的 O-GlcNAc 酰化可调节 FOXA1 的稳定性并促进其与染色质的组装。 O-GlcNAcylation 塑造 FOXA1 相互作用组，特别是触发转录抑制子甲基 CpG 结合蛋白 2 的募集，从而刺激 FOXA1 染色质结合位点切换到粘附相关基因（包括 EPB41L3 和 COL9A2）的染色质位点。 FOXA1 上 O-GlcNAcylation 的位点特异性缺失会影响各种下游基因的表达，从而在体外和体内抑制乳腺癌增殖和转移。我们的数据证实了异常 FOXA1 O-GlcNAcNA 酰化在乳腺癌进展中的重要性，并表明靶向 O-GlcNAcNA 酰化是转移性乳腺癌的一种治疗策略。 O-GlcNAcylation 修饰 FOXA1 相互作用组，诱导其染色质位点转换并引起转录变化。
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 Thr432, Ser441, and Ser443 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. O-GlcNAcylation modifies FOXA1 interactome, inducing switching of its chromatin loci and causing transcriptional changes.
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DOI：
10.1242/dev.199754
发表时间：
2021-08-01
期刊：
Development (Cambridge, England)
影响因子：
--
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影响因子：
3.3
作者：
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通讯作者：
Zou, Hanfa
影响因子：
4.8
作者：
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通讯作者：
Cirillo, Lisa Ann