Aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a rate-limiting enzyme involved in cellular retinoic acid synthesis. However, its functional role in ovarian cancer remains elusive. Here, we found that ALDH1A2 was the most prominently downregulated gene among ALDH family members in ovarian cancer cells, according to complementary DNA microarray data. Low ALDH1A2 expression was associated with unfavorable prognosis and shorter disease-free and overall survival for ovarian cancer patients. Notably, hypermethylation of ALDH1A2 was significantly higher in ovarian cancer cell lines when compared to that in immortalized human ovarian surface epithelial cell lines. ALDH1A2 expression was restored in various ovarian cancer cell lines after treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Furthermore, silencing DNA methyltransferase 1 (DNMT1) or 3B (DNMT3B) restored ALDH1A2 expression in ovarian cancer cell lines. Functional studies revealed that forced ALDH1A2 expression significantly impaired the proliferation of ovarian cancer cells and their invasive activity. To the best of our knowledge, this is the first study to show that ALDH1A2 expression is regulated by the epigenetic regulation of DNMTs, and subsequently that it might act as a tumor suppressor in ovarian cancer, further suggesting that enhancing ALDH1A2-linked signaling might provide new opportunities for therapeutic intervention in ovarian cancer.
Bibliographical noteFunding Information:
A total of 210 ovarian cancer, 56 borderline, 109 benign, and 71 nonadjacent normal epithelial tissues were obtained from patients at the Gangnam Severance Hospital between 1996 and 2010. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio and Medical Technology Development Program of the Ministry of the National Research Foundation (NRF), funded by the Korean government (MSIT) (NRF-2017M3A9B8069610). Tissue samples were collected from patients after they provided written informed consent, and the study was approved by the Regional Institutional Review Board of the Gangnam Severance Hospital (3-2018-0194). Ovarian cancer was staged according to the International Federation of Gynecology and Obstetrics (FIGO) classification and graded according to the World Health Organization grading system. Clinical and pathological records were reviewed to collect data including age, surgical procedure, survival time, survival status, tumor grade, and cell type. The response to therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) by spiral computed tomography .
Funding: This study was supported by grants from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare Affairs, Korea (HI17C1635), Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2017R1D1A1B03036265), and Bio and Medical Technology Development Program of the National Research Foundation, funded by the Korean government (MSIT) (NRF-2017M3A9B8069610).
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All Science Journal Classification (ASJC) codes
- Cancer Research