L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer

Jianpeng Xiao; Jie Wang; Jialun Li; Jie Xiao; Cui Cui Liu; Libi Tan; Yanhong Tu; Ruifang Yang; Yujie Pei; Minghua Wang; Jiemin Wong; Binhua P. Zhou; Jing Li; Jing Feng

doi:10.1038/s41467-024-55617-9

L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer

Jianpeng Xiao, Jie Wang, Jialun Li, Jie Xiao, Cui Cui Liu, Libi Tan, Yanhong Tu, Ruifang Yang, Yujie Pei, Minghua Wang, Jiemin Wong, Binhua P. Zhou, Jing Li, Jing Feng

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The STAT3 pathway promotes epithelial–mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial–mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial–mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis.

Original language	English
Article number	231
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-55617-9
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We thank Prof. Mingyao Liu and Prof. Zhengfang Yi from East China Normal University for providing cFUGW-Flag-STAT3Y705F and cFUGW-Flag-STAT3-C plasmids. We thank Prof. Jian Luo from Tongji University for providing pcDNA3-HA-STAT3 plasmid. We thank Prof. Arrowsmith from University of North Carolina at Chapel Hill for providing L3MBTL3 full-length plasmid GFP-L3MBTL3. This study was supported by grants from the National Natural Science Foundation of China (82173044, J.F. and 81772817, J.L.), Shanghai Medical Leadership Program (2019LJ25, J.F.), Medical and Health Technology Public Relations Project of Shenzhen Longgang District Science and Technology Innovation Special Fund (LGKCYLWS2022001, J.F.), Special Program for Collaborative Innovation in Shanghai University of Medicine & Health Sciences (SPCI-17\u201015\u2010001, J.F.), and Key Subject Construction Project of Shanghai Municipal Commission of Health and Family Planning, China (ZK2019B29, J.F.). The results shown here are in part based upon data generated by the TCGA Research Network: \u201Chttps://www.cancer.gov/tcga.\u201D We thank Prof. Mingyao Liu and Prof. Zhengfang Yi from East China Normal University for providing cFUGW-Flag-STAT3 and cFUGW-Flag-STAT3-C plasmids. We thank Prof. Jian Luo from Tongji University for providing pcDNA3-HA-STAT3 plasmid. We thank Prof. Arrowsmith from University of North Carolina at Chapel Hill for providing L3MBTL3 full-length plasmid GFP-L3MBTL3. This study was supported by grants from the National Natural Science Foundation of China (82173044, J.F. and 81772817, J.L.), Shanghai Medical Leadership Program (2019LJ25, J.F.), Medical and Health Technology Public Relations Project of Shenzhen Longgang District Science and Technology Innovation Special Fund (LGKCYLWS2022001, J.F.), Special Program for Collaborative Innovation in Shanghai University of Medicine & Health Sciences (SPCI-17\u201015\u2010001, J.F.), and Key Subject Construction Project of Shanghai Municipal Commission of Health and Family Planning, China (ZK2019B29, J.F.). The results shown here are in part based upon data generated by the TCGA Research Network: \u201C https://www.cancer.gov/tcga .\u201D

Funders	Funder number
University of North Carolina Wilmington
Tongji University
East China Normal University
Medical and Health Technology Public Relations Project of Shenzhen Longgang District Science and Technology Innovation Special Fund	LGKCYLWS2022001
Shanghai Municipal Health and Family Planning Commission	ZK2019B29
Shanghai Municipal Health and Family Planning Commission
Shanghai Medical Leadership Program	2019LJ25
National Natural Science Foundation of China (NSFC)	82173044, 81772817
National Natural Science Foundation of China (NSFC)
Special Program for Collaborative Innovation in Shanghai University of Medicine & Health Sciences	SPCI-17‐15‐001

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer",

abstract = "The STAT3 pathway promotes epithelial–mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial–mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial–mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis.",

author = "Jianpeng Xiao and Jie Wang and Jialun Li and Jie Xiao and Liu, \{Cui Cui\} and Libi Tan and Yanhong Tu and Ruifang Yang and Yujie Pei and Minghua Wang and Jiemin Wong and Zhou, \{Binhua P.\} and Jing Li and Jing Feng",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2025",

month = dec,

doi = "10.1038/s41467-024-55617-9",

language = "English",

volume = "16",

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AU - Xiao, Jianpeng

AU - Wang, Jie

AU - Li, Jialun

AU - Xiao, Jie

AU - Liu, Cui Cui

AU - Tan, Libi

AU - Tu, Yanhong

AU - Yang, Ruifang

AU - Pei, Yujie

AU - Wang, Minghua

AU - Wong, Jiemin

AU - Zhou, Binhua P.

AU - Li, Jing

AU - Feng, Jing

PY - 2025/12

Y1 - 2025/12

N2 - The STAT3 pathway promotes epithelial–mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial–mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial–mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis.

AB - The STAT3 pathway promotes epithelial–mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial–mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial–mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis.

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L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer

Abstract

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UN SDGs

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