Exp Mol Med.  2017 May;49(5):e335. 10.1038/emm.2017.62.

Aberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancer

• Sung HY
• Yang SD
• Ju W
• Ahn JH

• KMID: 2382697
• DOI: http://doi.org/10.1038/emm.2017.62

Abstract

Metastasis is a major cause of therapeutic failure in ovarian cancer. To elucidate molecular mechanisms of ovarian cancer metastasis, we previously established a metastatic xenograft mouse model using human ovarian carcinoma SK-OV-3 cells. Using gene expression profiling, we found that γ-aminobutyric acid (GABA)A receptor Ï€ subunit (GABRP) expression was upregulated (>4-fold) in metastatic tissues from our xenograft mice compared with SK-OV-3 cells. Importantly, GABRP knockdown diminished the migration and invasion of SK-OV-3 cells, and reduced extracellular signal-regulated kinase (ERK) activation while overexpression of GABRP exhibited significantly increased cell migration, invasion and ERK activation. Moreover, treatment with the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor U0126 similarly suppressed the migration and invasion of SK-OV-3 cells, implying that GABRP promotes these cellular behaviors by activating the MAPK/ERK pathway. Using genome-wide DNA methylation profiling, we identified hypomethylated CpG sites in the GABRP promoter in metastatic tissues from the xenograft mice compared with SK-OV-3 cells. Treatment with a DNA methyltransferase inhibitor demonstrated that methylation at −963"‰bp from the GABRP transcription start site (−963 CpG site) was critical for the epigenetic regulation of GABRP. Finally, we analyzed human ovarian cancer patient samples and showed DNA hypomethylation at the GABRP −963 CpG site in advanced stage, but not early-stage, primary tumors compared with their paired normal tissues. These findings suggest that GABRP enhances the aggressive phenotype of ovarian cancer cells, and that the DNA methylation status of the GABRP −963 CpG site may be useful for predicting the metastatic potential in ovarian cancer patients.

MeSH Terms

Animals
Cell Movement
DNA
DNA Methylation
Epigenomics*
Gene Expression Profiling
Heterografts
Humans
Methylation
Mice
Neoplasm Metastasis
Ovarian Neoplasms*
Phenotype*
Phosphotransferases
Protein Kinases
Transcription Initiation Site
DNA
Phosphotransferases
Protein Kinases