Youssef Emile M, Issa Jean-Pierre J, Lotan Reuben
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Cancer Biol Ther. 2004 Oct;3(10):1002-6. doi: 10.4161/cbt.3.10.1139. Epub 2004 Oct 2.
Retinoids have shown significant activities in cancer prevention and therapy. Many of their effects are mediated by nuclear retinoid receptors including retinoic acid receptors (RARs alpha, beta and gamma) and retinoid X receptors (RXRs alpha, beta and gamma). Human retinoic acid receptor beta (RARbeta) has three different isoforms: beta1, beta2 and beta4. The tumor suppressive characteristics of RARbeta2, its silencing by promoter hypermethylation, and its reexpression following demethylation have been reported. In contrast, RARbeta1, an embryonic isoform with restricted expression in adult tissues has been linked to carcinogenesis. However, factors regulating RARbeta1 expression have not yet been clarified. During studies on the head and neck squamous cell carcinoma cells, we found that the expression of RARbeta increased in cells grown to high density. Real-time reverse-transcriptase polymerase chain reaction revealed that the isoform increased in these cells was RARbeta1. Epigenetic modifications of this isoform were tested using combined bisulfite restriction analysis and chromatin immunoprecipitation assays. The UMSCC38 cell line showed significant RARbeta1 expression (p < 0.001), which was dependent on cell density and culture duration. The increased expression of RARbeta1 was not due to demethylation of its promoter. However, higher cell densities were associated with increased acetylation of histone 3 at lysine 9 in RARbeta1 but not in RARbeta2. These findings reveal that the expression of RARbeta1 is regulated by cell density through changes in histone acetylation.
维甲酸在癌症预防和治疗中已显示出显著活性。它们的许多作用是由核维甲酸受体介导的，包括维甲酸受体（RARα、β和γ）和维甲酸X受体（RXRα、β和γ）。人类维甲酸受体β（RARβ）有三种不同的亚型：β1、β2和β4。RARβ2的肿瘤抑制特性、其启动子高甲基化导致的沉默以及去甲基化后的重新表达均有报道。相比之下，RARβ1是一种在成体组织中表达受限的胚胎亚型，与致癌作用有关。然而，调节RARβ1表达的因素尚未阐明。在对头颈部鳞状细胞癌细胞的研究中，我们发现当细胞生长至高密度时，RARβ的表达增加。实时逆转录聚合酶链反应显示，在这些细胞中增加的亚型是RARβ1。使用亚硫酸氢盐联合限制性分析和染色质免疫沉淀试验检测了该亚型的表观遗传修饰。UMSCC38细胞系显示出显著的RARβ1表达（p < 0.001），这取决于细胞密度和培养时间。RARβ1表达的增加并非由于其启动子的去甲基化。然而，更高的细胞密度与RARβ1中赖氨酸9处组蛋白3的乙酰化增加有关，而RARβ2中则没有。这些发现表明，RARβ1的表达通过组蛋白乙酰化的变化受细胞密度调节。
