Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Epigenetics. 2012 Apr;7(4):390-9. doi: 10.4161/epi.19373. Epub 2012 Apr 1.
CD1d is a MHC class-like molecule that presents glycolipids to natural killer T (NKT) cells, then regulates innate and adaptive immunity. The regulation of CD1d gene expression in solid tumors is still largely unknown. Gene expression can be epigenetically regulated by DNA methylation and histone acetylation. We found that histone deacetylase inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), induced CD1d gene expression in human (A549 and NCI-H292) and mouse (TC-1 and B16/F0) cancer cells. Simultaneous knockdown of HDAC1 and 2 induced CD1d gene expression. Sp1 inhibitor mitramycin A (MTM) blocked TSA- and SAHA-induced CD1d mRNA expression and Sp1 luciferase activity. Co-transfection of GAL4-Sp1 and Fc-luciferase reporters demonstrated that TSA and SAHA induced Sp1 luciferase reporter activity by enhancing Sp1 transactivation activity. The binding of Sp1 to CD1d promoter and histone H3 acetylation on Sp1 sites were increased by TSA and SAHA. These results indicate that TSA and SAHA could up-regulate CD1d expression in tumor cells through inhibition of HDAC1/2 and activation of Sp1.
CD1d 是一种 MHC 类样分子，它将糖脂递呈给自然杀伤 T（NKT）细胞，从而调节先天和适应性免疫。实体瘤中 CD1d 基因表达的调控在很大程度上仍不清楚。基因表达可以通过 DNA 甲基化和组蛋白乙酰化的表观遗传调控。我们发现组蛋白去乙酰化酶抑制剂曲古抑菌素 A（TSA）和丙戊酸（SAHA）诱导人（A549 和 NCI-H292）和鼠（TC-1 和 B16/F0）癌细胞中 CD1d 基因的表达。HDAC1 和 2 的同时敲低诱导 CD1d 基因的表达。Sp1 抑制剂米托霉素 A（MTM）阻断 TSA 和 SAHA 诱导的 CD1d mRNA 表达和 Sp1 荧光素酶活性。GAL4-Sp1 和 Fc-荧光素酶报告基因的共转染表明，TSA 和 SAHA 通过增强 Sp1 反式激活活性诱导 Sp1 荧光素酶报告基因的活性。TSA 和 SAHA 增加了 Sp1 与 CD1d 启动子的结合以及 Sp1 结合位点上的组蛋白 H3 乙酰化。这些结果表明，TSA 和 SAHA 可以通过抑制 HDAC1/2 和激活 Sp1 来上调肿瘤细胞中 CD1d 的表达。
