title: The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer.
abstract: BACKGROUND
  Emerging evidence suggests that G9a, a histone methyltransferase, is involved in tumor progression and metastasis. However, the functional significance of G9a in endometrial carcinogenesis has not been defined.
  
  
  METHODS
  The differential expression of G9a in cancer and normal tissues was assessed using an array of 28 paired samples. Tissue specimens from 94 patients with endometrial cancer who underwent primary surgery were immunohistochemically evaluated for G9a and E-cadherin expression. To assess the biologic role of G9a in endometrial cancer, G9a was either stably knocked down or knocked down using a tetracycline-controllable system in endometrial cancer cells, followed by functional assays.
  
  
  RESULTS
  Increased G9a expression was identified in endometrial cancer tissues, and its expression was specifically correlated with deep myometrial invasion. Cell invasiveness was inhibited by an RNAi-mediated knockdown of G9a in invasive endometrial cancer cells in vitro and in vivo. An important mediator of G9a-induced tumor invasion is the epigenetic silencing of E-cadherin. Knockdown of G9a restored E-cadherin expression by reducing H3K9me2 levels and decreasing CDH1 promoter DNA methyltransferase recruitment. Knockdown of RNAi-mediated E-cadherin substantially relieved the invasion suppression imposed by G9a suppression. A significant negative correlation between G9a and E-cadherin expression was observed in endometrial cancer (Spearman's rho, -0.27; P = 0.02).
  
  
  CONCLUSIONS
  This study provides the first clear evidence that G9a contributes to endometrial cancer progression. Mechanistic investigations suggest that E-cadherin repression mediates the effects of G9a. Targeting G9a-mediated epigenetic pathway dysregulation may be a therapeutic strategy for endometrial cancers.
authors.affiliation: Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Sheng-Mou
authors.initials: SM
authors.lastname: Hsiao
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chi-An
authors.initials: CA
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.|Wan Fan Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. weilh1966@gmail.com.|Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan. weilh1966@gmail.com.
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009215:Myometrium / Q000378:metabolism / Q000473:pathology*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D006649:Histocompatibility Antigens; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase