Aberrant Hypomethylation of Solute Carrier Family 6 Member 12 Promoter Induces Metastasis of Ovarian Cancer.
- Author:
Hye Youn SUNG
1
;
San Duk YANG
;
Ae Kyung PARK
;
Woong JU
;
Jung Hyuck AHN
Author Information
- Publication Type:Original Article
- Keywords: Ovarian cancer; metastasis; mouse xenograft; SLC6A12; DNA methylation
- MeSH: Animals; Carrier Proteins/genetics/*metabolism; Cell Line, Tumor; Cell Migration Assays; *CpG Islands; *DNA Methylation; Disease Progression; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; Ovarian Neoplasms/genetics/*metabolism/mortality/pathology; Polymerase Chain Reaction; Prognosis; *Promoter Regions, Genetic; RNA, Messenger/*metabolism; Up-Regulation
- From:Yonsei Medical Journal 2017;58(1):27-34
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Ovarian cancer (OC) is the most fatal of gynecological malignancies with a high rate of recurrence. We aimed to evaluate the expression of solute carrier family 6, member 12 (SLC6A12) and methylation of its promoter CpG sites in a xenograft mouse model of metastatic OC, and to investigate the regulatory mechanisms that promote aggressive properties during OC progression. MATERIALS AND METHODS: Expression of SLC6A12 mRNA was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and DNA methylation status of its promoter CpGs was detected by quantitative methylation-specific PCR. The metastatic potential of SLC6A12 was evaluated by in vitro migration/invasion transwell assays. Gene expression and DNA methylation of SLC6A12 and clinical outcomes were further investigated from publicly available databases from curatedOvarianData and The Cancer Genome Atlas. RESULTS: SLC6A12 expression was 8.1–14.0-fold upregulated and its DNA methylation of promoter CpG sites was 41–62% decreased in tumor metastases. After treatment with DNA methyltransferase inhibitor and/or histone deacetylase inhibitor, the expression of SLC6A12 was profoundly enhanced (~8.0-fold), strongly supporting DNA methylation-dependent epigenetic regulation of SLC6A12. Overexpression of SLC6A12 led to increased migration and invasion of ovarian carcinoma cells in vitro, approximately 2.0-fold and 3.3-fold, respectively. The meta-analysis showed that high expression of SLC6A12 was significantly associated with poor overall survival [hazard ratio (HR)=1.07, p value=0.016] and that low DNA methylation levels of SLC6A12 at specific promoter CpG site negatively affected patient survival. CONCLUSION: Our findings provide novel evidence for the biological and clinical significance of SLC6A12 as a metastasis-promoting gene.
