The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis
Journal
Molecular Cancer
Journal Volume
13
Journal Issue
1
Date Issued
2014
Author(s)
Wang M.-Y
Chen M.-W
Chen C.-K
Ko C.-H
Sung P.-L
Jan Y.-H
Hsiao M
Kuo M.-L
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.Method: 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.Conclusion: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease. ? 2014 Hua et al.; licensee BioMed Central Ltd.
SDGs
Other Subjects
histone methyltransferase; histone methyltransferase G9a; unclassified drug; EHMT2 protein, human; histocompatibility antigen; histone; histone lysine methyltransferase; lysine; tumor marker; anoikis; Article; ascites; biological functions; cdh1 gene; cell adhesion; cell invasion; cell migration; dusp5 gene; female; human; metastasis; ovarian cancer cell line; ovary cancer; peritoneum metastasis; ppp1r15a gene; primary tumor; reverse transcription polymerase chain reaction; spry4 gene; tumor suppressor gene; animal; cell motion; disease course; enzymology; gene expression regulation; gene silencing; genetics; metabolism; multivariate analysis; nonobese diabetic mouse; ovary tumor; pathology; peritoneum tumor; prognosis; SCID mouse; secondary; signal transduction; tumor cell line; tumor invasion; Animals; Anoikis; Biomarkers, Tumor; Cell Adhesion; Cell Line, Tumor; Cell Movement; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Mice, Inbred NOD; Mice, SCID; Multivariate Analysis; Neoplasm Invasiveness; Ovarian Neoplasms; Peritoneal Neoplasms; Prognosis; Signal Transduction
Type
journal article