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Aberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancer
- Aberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancer
- Sung, Hye Youn; Yang, San-Duk; Ju, Woong; Ahn, Jung-Hyuck
- Ewha Authors
- 주웅; 안정혁; 성혜윤
- SCOPUS Author ID
- 주웅; 안정혁; 성혜윤
- Issue Date
- Journal Title
- EXPERIMENTAL AND MOLECULAR MEDICINE
- 1226-3613; 2092-6413
- vol. 49
- NATURE PUBLISHING GROUP
- SCI; SCIE; SCOPUS; KCI
- 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 gamma-aminobutyric acid (GABA) A receptor pi subunit (GABRP) expression was upregulated (44-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.
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