Abstract
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.
Highlights
Ovarian cancer has the highest mortality rate among all gynecological cancers because most cases are not diagnosed until the disease has reached an advanced stage [1]
Aldehyde dehydrogenase 1 family member A2 (ALDH1A2), ALDH1B1, and ALDH9A1 were downregulated in the ovarian cancer cells compared to the expression in human ovarian surface epithelial (HOSE) cells (Figure 1A and Table S1), whereas ALDH3A1 was upregulated in the ovarian cancer cells
DNMT3B in ovarian cancer cell lines, indicating that ALDH1A2 expression is regulated by epigenetic regulation via DNA methyltransferases (DNMTs)
Summary
Ovarian cancer has the highest mortality rate among all gynecological cancers because most cases are not diagnosed until the disease has reached an advanced stage [1]. The five-year survival rate for ovarian cancer patients has substantially improved, owing to ongoing efforts to develop an effective screening strategy [1], the lack of reliable methods for early diagnosis and the absence of specific symptoms result in diagnoses at advanced stages [1]. Approximately 80% of women with advanced ovarian cancer show tumor progression or, more commonly, recurrence [2]. Understanding the pathogenesis of ovarian cancer and the molecular mechanism of its early stage is crucial for the management of this lethal, highly metastatic disease.
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