The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis

Abstract

BackgroundOvarian 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.MethodThe 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.ResultsWe 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.ConclusionWe propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-189) contains supplementary material, which is available to authorized users.

G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma

“…Thus, targeting Snail–G9a axis may represent a novel approach for treating and/or preventing metastatic HNSCC. Many cancers show an upregulation of both Snail and G9a including HNSCC [31, 32, 57]. Because either knockdown of G9a expression or suppression by BIX01294 inhibits migration and tumorsphere formation, targeting Snail and G9a, or their interaction, may repress EMT and the stem cell-like properties in HNSCC.…”

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

“…Indeed, overexpression and gene amplification of G9a were observed in a number of human cancers, but GLP was observed in only a few cases (54). In addition, G9a, not GLP, was often evaluated as a marker of aggressive cancers (55)(56)(57). For these reasons, we performed an in vivo metastasis experiment using ovarian cancer cell lines overexpressing G9a or its NQ-mutant, and successfully showed the involvement of the FIH/G9a axis in cancer metastasis (Fig.…”

Exploring Serologic Indicators for Laboratory Diagnosis of Asymptomatic Neurosyphilis

“…For example, histone methyltransferase G9a is overexpressed in different types of carcinomas, including ovarian cancer, AML and lung cancer [12][13][14]. As epigenetically G9a is able to modify H3K9me2 at euchromatin regions and protect DNA methylation at imprinted control regions (ICRs) [15,16], the aberrant distribution of epigenetic markers might directly result in the initiation and development of carcinomas in humans.…”