title: Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer.
abstract: OBJECTIVE
  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.
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China.
authors: Jingxin
authors: J
authors: Feng
authors: The Breast Surgery, The Tumor Hospital of Jilin Province, Changchun, 130000, China.
authors: Guiying
authors: G
authors: Xu
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China.
authors: Jiwei
authors: J
authors: Liu
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China.
authors: Na
authors: N
authors: Zhang
authors: 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.
authors: Lili
authors: L
authors: Li
authors: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China.
authors: Jiafei
authors: J
authors: Ji
authors: 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.
authors: Jianchao
authors: J
authors: Zhang
authors: Department of Pathology, The Second Hospital of Jilin University, Changchun, 130041, China.
authors: Lian
authors: L
authors: Zhang
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China.
authors: Guannan
authors: G
authors: Wang
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China.
authors: Xiuli
authors: X
authors: Wang
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China.
authors: Jiang
authors: J
authors: Tan
authors: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China.
authors: Baiqu
authors: B
authors: Huang
authors: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China.
authors: Jun
authors: J
authors: Lu
authors: The Institute of Genetics and Cytology, Northeast Normal University, No.5268 Renmin Street, Changchun, 130024, China. zhangy288@nenu.edu.cn.
authors: Yu
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012694:Serine / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D006657:Histones; D012694:Serine; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Breast cancer; EMT; LSD1; Metastasis; Phosphorylation