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

Title
Aberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancer
Authors
Sung, Hye YounYang, San-DukJu, WoongAhn, Jung-Hyuck
Ewha Authors
주웅안정혁성혜윤
SCOPUS Author ID
주웅scopus; 안정혁scopus; 성혜윤scopus
Issue Date
2017
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
1226-3613JCR Link2092-6413JCR Link
Citation
vol. 49
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS; KCI WOS
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 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.
DOI
10.1038/emm.2017.62
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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