Research Institute of Occlusion Medicine and Open Research Center, Kanagawa Dental College, Yokosuka, Japan.
J Pathol. 2011 Jul;224(3):420-9. doi: 10.1002/path.2878. Epub 2011 Apr 19.
DEC1 (also known as Stra13/Bhlhb2/Sharp2) and DEC2 (also known as Bhlhb3/Sharp1) are two paralogous basic helix-loop-helix (bHLH) transcriptional regulators which exhibit a robust circadian gene expression pattern in the suprachiasmatic nucleus (SCN) and in peripheral organs. DEC1 has been suggested to play key roles in mammalian cell differentiation, the cell cycle and circadian regulation, hypoxia response, and carcinogenesis. Here we show that DEC1 overexpression exhibits delayed wound healing and reduces cell proliferation, migration, and invasion. DEC1 strongly repressed the promoter activity of cyclin D1. We further identify a possible DEC-response element in the cyclin D1 promoter region, and confirmed the direct binding of DEC1 to that element. Forced expression of DEC1 efficiently repressed the cyclin D1 promoter and expression. Our clinical data provide the first evidence that there is a strong inverse correlation between DEC1 and cyclin D1 expression in oral cancer, and DEC1 expression significantly correlated with clinicopathological parameters. We suggest that radiation-induced DEC1 overexpression and Akt phosphorylation in cancer cells are mediated via PI-3K signalling. Overexpression of DEC1 activates the PI-3K/Akt signalling pathway through reactive oxygen species (ROS).
DEC1（也称为 Stra13/Bhlhb2/Sharp2）和 DEC2（也称为 Bhlhb3/Sharp1）是两种同源的基本螺旋-环-螺旋（bHLH）转录调节因子，它们在视交叉上核（SCN）和外周器官中表现出强大的昼夜节律基因表达模式。DEC1 被认为在哺乳动物细胞分化、细胞周期和昼夜节律调节、缺氧反应和致癌作用中发挥关键作用。在这里，我们表明 DEC1 的过表达表现出延迟的伤口愈合，并减少细胞增殖、迁移和侵袭。DEC1 强烈抑制细胞周期蛋白 D1 的启动子活性。我们进一步鉴定了细胞周期蛋白 D1 启动子区域中可能的 DEC 反应元件，并证实了 DEC1 与该元件的直接结合。DEC1 的强制表达有效地抑制了细胞周期蛋白 D1 启动子和表达。我们的临床数据首次提供了证据，表明口腔癌中 DEC1 和细胞周期蛋白 D1 的表达呈强烈负相关，并且 DEC1 的表达与临床病理参数显著相关。我们认为，癌细胞中 DEC1 的辐射诱导过表达和 Akt 磷酸化是通过 PI-3K 信号传导介导的。DEC1 的过表达通过活性氧（ROS）激活 PI-3K/Akt 信号通路。
