The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer.
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-2'-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.
Kim
Hanna
H
Department of Pathology, Stanford University, Stanford, California 94305-5176, USA.
Lapointe
Jacques
J
Kaygusuz
Gulsah
G
Ong
David E
DE
Li
Chunde
C
van de Rijn
Matt
M
Brooks
James D
JD
Pollack
Jonathan R
JR
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050697:Retinal Dehydrogenase; D014212:Tretinoin / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014212:Tretinoin; D000077209:Decitabine; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D001374:Azacitidine