title: The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis.
abstract: BACKGROUND
  Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood.
  
  
  METHODS
  The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes.
  
  
  RESULTS
  We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens.
  
  
  CONCLUSIONS
  We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Wang
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
authors.forename: Chi-Kuan
authors.initials: CK
authors.lastname: Chen
authors.forename: Ching-Huai
authors.initials: CH
authors.lastname: Ko
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Pi-Lin
authors.initials: PL
authors.lastname: Sung
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan. kuominliang@ntu.edu.tw.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.forename: Men-Luh
authors.initials: ML
authors.lastname: Yen
mesh_terms: D000818:Animals; D023102:Anoikis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary*; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D006649:Histocompatibility Antigens; D006657:Histones; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine