ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer

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.

Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells

“…These data are in agreement with our previous work showing that ALDH1A2, relative to ALDH1A1, was more enriched in OV90 TICs and contributed to spheroid formation [ 21 ]. Recent findings demonstrating that ALDH1A2 [ 41 ] suppresses the proliferation of ovarian cancer cells may highlight its role in maintaining quiescence of the TIC population, as suggested by our studies.…”

“…Interestingly, the ALDH1A2 gene, unlike the other markers, was enhanced in 3-D cultures relative to 2-D cultures of OVCAR5 and OV90 lines and ALDH1A1 was enhanced in all lines tested. This may be explained by the dependence of certain cells on different ALDH enzymes, a family comprised of 19 isozymes [ 35 ], and the corresponding differences in the endogenous expression of these genes across ovarian cancer cell lines shown by this study and others [ 14 , 41 ]. These data are in agreement with our previous work showing that ALDH1A2, relative to ALDH1A1, was more enriched in OV90 TICs and contributed to spheroid formation [ 21 ].…”

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

“…Zhao et al found that the increased expression of DNMT3B in ovarian cancer cells increased the methylation level of the promoter regions of anti-oncogenes such as hMLH1 (mismatch repair gene human mutL homolog-1), p16 and p53 . These methylation changes decreased the expression of the hMLH1 , p16 and p53 genes and promoted tumor development [ 42 , 107 ]. As mentioned above, decitabine is a specific DNMT inhibitor, which can partially reverse DNA methylation.…”

Applications of Multi-omics Approaches for Exploring the Molecular Mechanism of Ovarian Carcinogenesis

“…One study demonstrated that creatine kinase B (CKB) was upregulated in OC cells compared with normal ovary surface epithelial cells by cDNA microarray analysis (61). Moreover, 24957 genes were dysregulated between OC cells and normal ovarian cells by cDNA microarray analysis (62). Fifteen ALDH (aldehyde dehydrogenase) isoforms exhibited differential expression patterns; for example, the downregulation of ALDH1A2 (aldehyde dehydrogenase 1 family member A2), ALDH1B1 and ALDH9A1 and the upregulation of ALDH3A1 were observed in OC cells (62).…”