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Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

LSD1 is overexpressed in various cancers including breast cancer, but its functional roles in tumourigenesis are not fully understood. This study aims at revealing the role of LSD1 in breast cancer development. In addition, it has been reported that phosphorylation of the Serine 112 residue of LSD1 by PKCα is crucial for its function in gene regulation. We also explored whether this phosphorylation affects LSD1’s role in breast cancer development.

Methods

This study includes LSD1 IHC data generated with tissue microarrays of 163 cases of breast cancer samples and 72 normal tissues. In vitro, role of LSD1, LSD1 S112D mutant (a phosphorylation simulation) and LSD1 S112A mutant (an unphosphorylation simulation) in induction of EMT is evaluated. Mechanismly, we checked the role of LSD1 and its mutant on E-cadherin promoter histone modifications. We also investigated the role of LSD1 and its mutants in metastasis with a nude mice model.

Results

We found LSD1 is expressed at a higher level in breast cancer tissues compared with that in normal tissues, and LSD1 expression is closely linked to breast cancer metastasis. LSD1 potentiates EMT in breast epithelia cells by repressing E-cadherin expression through demethylating H3K4me at gene’s promoter, during which phosphorylation of LSD1 Ser112 is crucial for its binding and demethylation activity. In vivo, knockdown of LSD1 impairs the metastatic ability of MDA-MB-231 breast cancer cells in nude mice. Ectopic overexpression of either LSD1 or LSD1 S112D mutant (a phosphorylation simulation) facilitates metastasis, whereas the LSD1 S112A mutant (an unphosphorylation simulation) fails to affect the metastasis.

Conclusions

Data presented in this report indicate that LSD1 is able to induce EMT and to promote metastasis in breast cancer, and phosphorylation at LSD1 Ser112 is crucial for these functions.

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Acknowledgments

We thank Dr. Huang Wei from the School of Mathematics and Statistics of Northeast Normal University for kindly providing statistical analysis guidance. This work was supported by the grants from the National Natural Science Foundation of China (Grant Numbers 31570718, 31571478, 31571317, 31371294, 31271442 and 31401105) and from Jilin Scientific and Technological Development Program (Grant Numbers 20140520003JH and 20160101157JC). We also acknowledge the support from the “Program for Introducing Talents to Universities” (B07017) in assistance of international cooperation.

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Authors and Affiliations

  1. The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China

    Jingxin Feng, Jiwei Liu, Na Zhang, Xiuli Wang, Jiang Tan & Yu Zhang

  2. The Breast Surgery, The Tumor Hospital of Jilin Province, Changchun, 130000, China

    Guiying Xu

  3. Key Laboratory of Cancer Prevention and Therapy, Department of Bone and Soft Tissue Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300202, China

    Lili Li

  4. The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China

    Jiafei Ji, Baiqu Huang & Jun Lu

  5. Shenzhen Key Laboratory for Molecular Biology of Neural Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China

    Jianchao Zhang

  6. Department of Pathology, The Second Hospital of Jilin University, Changchun, 130041, China

    Lian Zhang

  7. National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China

    Guannan Wang

Authors
  1. Jingxin Feng
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  2. Guiying Xu
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  3. Jiwei Liu
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  4. Na Zhang
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  5. Lili Li
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  6. Jiafei Ji
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  7. Jianchao Zhang
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  8. Lian Zhang
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  10. Xiuli Wang
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  11. Jiang Tan
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  13. Jun Lu
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  14. Yu Zhang
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Corresponding author

Correspondence to Yu Zhang.

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The authors disclose no potential conflicts of interest.

Authors’ contributions

J.F. contributed concept, designed and performed the experiments, analyzed the data and co-wrote the manuscript. GX, JL, NZ, LL and JJ participated in performing the experiments on breast cancer cell lines. LZ participated in IHC study. GW participated in athymismus mouse transplantation study. JZ, XW and JT made critical comments about the experiment designs. JL, BH and YZ supervised the project, participated in conception, design and data analysis and co-wrote the manuscript.

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Feng, J., Xu, G., Liu, J. et al. Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer. Breast Cancer Res Treat 159, 443–456 (2016). https://doi.org/10.1007/s10549-016-3959-9

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