3-Oxoacid CoA transferase 1 as a therapeutic target gene for cisplatin-resistant ovarian cancer.

Abstract

Ovarian cancer (OC) is the second leading cause of mortality from gynecological malignancies and has the highest mortality rate worldwide. As it is commonly asymptomatic during the early stages of the disease, >70% of patients with OC are diagnosed at advanced stages with metastasis. Despite treatment methods, including optimal debulking surgery and chemotherapy with the platinum-based drug cisplatin, OC recurrence is often inevitable, with an overall 5-year survival rate of 45%, mostly due to the steady development of cisplatin resistance. To identify genes involved in cisplatin resistance, the present study determined the half-maximal inhibitory concentrations of eight different OC cell lines and classified them into two groups (sensitive and resistant). mRNA expression was analyzed with GeneChip Human Gene 1.0 ST Arrays, and DNA methylation profiles were evaluated with the HumanMethylation450 BeadChip. Using an integrated approach of analyzing gene expression levels and DNA methylation profiles simultaneously, 26 genes were selected that were differentially expressed and methylated between the resistant and sensitive groups. Among these 26 genes, 3-oxoacid CoA transferase 1 (OXCT1), which was demonstrated to be downregulated and hypermethylated at promoter CpGs in the cisplatin-resistant group compared with the cisplatin-sensitive group, was selected for further investigation. Treatment with a DNA methyltransferase inhibitor restored hypermethylation-mediated gene silencing of OXCT1 in the cisplatin-resistant group, but not in the cisplatin-sensitive group. Furthermore, overexpression of OXCT1 conferred sensitivity to cisplatin in OC cells. The results of the present study suggest that OXCT1 serves an important role in conferring cisplatin sensitivity, and may provide a potential therapeutic target for cisplatin chemotherapy in patients with recurrent OC.