The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer
The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer
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DOI：
10.1158/0008-5472.can-04-4562
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Pollack, JR
中科院分区：
文献类型：
--
作者：
Kim, H;Lapointe, J;Pollack, JR
前列腺癌是美国男性中最常见的癌症，而异常的DNA甲基化是其发展的早期分子事件。在这里，我们使用表达谱来鉴定新的高甲基化基因，这些基因的表达是由DNA甲基转移酶抑制剂5-Aza-2'-脱氧胞苷（5-aza-dC）治疗前列腺癌细胞诱导的。在5-aza-dC治疗诱导的271个基因中，与正常前列腺组织相比，25个基因在原发性前列腺肿瘤中也表现出表达降低，并且只有醛脱氢酶I家族成员A2 （ALDH1a2）的表达降低也与较短的无复发生存期相关。ALDH1a2编码一种酶，负责合成维甲酸（RA），一种具有前分化特性的化合物。通过免疫组化，我们观察到ALDH1a2在正常前列腺上皮中表达，而在前列腺癌中不表达。通过亚硫酸氢盐测序，我们确定ALDH1a2启动子区域在原发性前列腺肿瘤中与正常前列腺标本相比显著高甲基化（P = 0.01）。最后，在前列腺癌细胞系DU145中，转染介导的野生型ALDH1a2（但不是推定的催化死亡突变体）的重表达导致集落生长下降（P < 0.0001），与5-aza-dC或RA治疗相当。综上所述，我们的研究结果表明ALDH1a2是前列腺癌的候选肿瘤抑制基因，并进一步支持类维生素a在预防或治疗前列腺癌中的作用。
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 I 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.