The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Abstract

Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2V-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1a2), was also associated with shorter recurrence-free survival. ALDH1a2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1a2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1a2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1a2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1a2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer. (Cancer Res 2005; 65(18): 8118-24)

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

“…In the present study, we investigated potential alterations in the RA pathway and analyzed their clinical relevance. In contrast to findings in other tumor entities, [7][8][9][10][11][12][13][14] we observed a marked up-regulation of key molecules associated with increased RA availability and alternative, prosurvival RA usage in gliomas. This was accompanied by increased intratumoral levels of RA precursors and activated RA.…”

“…[7][8][9][10][11][12][13][14] In particular, epithelial tumors, which originate from tissues that depend on a closely orchestrated balance between cellular proliferation and subsequent differentiation, show loss of RA signaling components involved in RA availability. This frequently includes altered expression of cellular retinolbinding protein 1 (CRBP1), an intracellular transport protein in charge of facilitating the uptake of RA precursor molecules, [7][8][9] and of aldehyde dehydrogenase 1A1 (ALDH1A1), which is capable of activating RA precursors into the active RA metabolite, 10,11 as well as of cellular retinoic acid binding protein 2 (CRABP2) and cellular retinoic acid binding protein 1 (CRABP1), two chaperone proteins that shuttle between different cellular compartments channeling RA to designated nuclear RA receptors or to endosomal degradation by cytochrome P450, family 26 members (CYP26), respectively. [12][13][14] In addition, recent studies on breast tumor cells revealed a pathological involvement of the intracellular transport protein fatty acid binding protein 5 (FABP5) in neoplastic RA signaling.…”

Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance

“…It functions as a detoxifying enzyme and has been proposed as a common marker for both normal and malignant stem and progenitor cells (17,19,27). ALDH1 activity has been employed successfully as a stem cell marker in retinoblastoma, prostate, pancreas and breast cancer (20,(28)(29)(30). The current study demonstrated that both human osteosarcoma MG63 and human fibrosarcoma HT1080 contained subpopulations with high ALDH activity, approximately 10% of the total cell population, as determined by Aldefluor assay.…”

Discovery of microarray-identified genes associated with ovarian cancer progression

“…ALDH1A2 encodes an enzyme responsible for the synthesis of retinoic acid, a compound with prodifferentiation properties. ALDH1A2 is identified to be a candidate TSG in prostate cancer whose expression is induced by DNA demethylation, which is reduced in prostate tumors compared with normal prostate, and negatively correlated with tumor-free survival (57). A further study indicate that ALDH1A2 is involved in apoptosis in bladder cancer cells (58), and has significant effects on cell proliferation and drug resistance in leukemia (59,60) and lung cancer cell lines (59).…”