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

Liu, Yajie1; Yu, Kairan1; Kong, Xiaotian2,3; Zhang, Keren4; Wang, Lingyan1; Zhang, Nana1; Chen, Qiushi5,6; Niu, Mingshan7; Li, Wenli1; Zhong, Xiaomin8; Wu, Sijin9; Zhang, Jianing1; Liu, Yubo1

2023-08-01

10.1126/sciadv.adg7112

SCIENCE ADVANCES   影响因子和分区

2375-2548

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.

SCI ; EI

英语

NI论文

其他

National Natural Science Foundation of China[31971214] ; Fundamental Research Funds for the Central Universities[DUT22YG131]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001050899400008

AMER ASSOC ADVANCEMENT SCIENCE

20233914802514

Diseases ; Pathology ; Transcription

Medicine and Pharmacology:461.6 ; Biology:461.9 ; Biochemistry:801.2

Web of Science

1.Dalian Univ Technol, Sch Life & Pharmaceut Sci, Panjin, Peoples R China
2.Beijing Univ Technol, Fac Environm & Life, Beijing, Peoples R China
3.Beijing Int Sci & Technol Cooperat Base Intelligen, Beijing, Peoples R China
4.Southern Univ Sci & Technol, Coll Sci, Dept Chem, Shenzhen, Peoples R China
5.Univ Hong Kong, Dept Chem, Hong Kong, Peoples R China
6.Lab Synthet Chem & Chem Biol Ltd, Hong Kong Sci Pk,Sci Pk West Ave, Hong Kong, Peoples R China
7.Xuzhou Med Univ, Blood Dis Inst, Xuzhou, Jiangsu, Peoples R China
8.Nanjing Med Univ, Affiliated Huaian Peoples Hosp No 1, Dept Oncol, Huaian, Peoples R China
9.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian, Peoples R China

Liu, Yajie,Yu, Kairan,Kong, Xiaotian,et al. FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer[J]. SCIENCE ADVANCES,2023,9(33).

Liu, Yajie.,Yu, Kairan.,Kong, Xiaotian.,Zhang, Keren.,Wang, Lingyan.,...&Liu, Yubo.(2023).FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer.SCIENCE ADVANCES,9(33).

Liu, Yajie,et al."FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer".SCIENCE ADVANCES 9.33(2023).