Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Division of Virology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2633-2646. doi: 10.1016/j.bbadis.2019.07.001. Epub 2019 Jul 8.
N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor that is frequently downregulated in adult T-cell leukemia/lymphoma (ATLL) and functions to negatively regulate several cellular signaling pathways as PP2A recruiter. To clarify the molecular mechanisms of suppression of NDRG2 expression, we initially determined the expression pattern of NDRG2 in various types of T-cells and ATLL cells. NDRG2 expression was significantly upregulated in HTLV-1/Tax-immortalized T-cells, which was mediated by NF-κB activation through Tax expression. On the other hand, NDRG2 expression was suppressed in HTLV-1-infected cell lines and various types of ATLL cells, which was dependent on the DNA methylation of the NDRG2 promoter. We found that the expression of enhancer of zeste homolog 2 (EZH2), a member of the polycomb family, is increased in ATLL, and that EZH2 directly binds to the NDRG2 promoter and induces DNA methylation of the NDRG2 promoter. Since the expression of EZH2 were anti-parallelly regulated with the NDRG2 expression, EZH2 might be one of the most important regulators of the downregulation of NDRG2, contributing to enhanced activation of signaling pathways during ATLL development.
N-myc 下游调节基因 2（NDRG2）是一种候选肿瘤抑制因子，在成人 T 细胞白血病/淋巴瘤（ATLL）中经常下调，其作为蛋白磷酸酶 2A（PP2A）募集物的功能，负调控多个细胞信号通路。为了阐明 NDRG2 表达抑制的分子机制，我们最初确定了 NDRG2 在各种类型 T 细胞和 ATLL 细胞中的表达模式。NDRG2 的表达在 HTLV-1/Tax 永生化 T 细胞中显著上调，这是通过 Tax 表达激活 NF-κB 介导的。另一方面，NDRG2 的表达在 HTLV-1 感染的细胞系和各种类型的 ATLL 细胞中受到抑制，这依赖于 NDRG2 启动子的 DNA 甲基化。我们发现，多梳家族成员增强子的锌指蛋白 2（EZH2）在 ATLL 中的表达增加，并且 EZH2 直接结合到 NDRG2 启动子上，并诱导 NDRG2 启动子的 DNA 甲基化。由于 EZH2 的表达与 NDRG2 的表达呈反平行调节，因此 EZH2 可能是 NDRG2 下调的最重要调节因子之一，有助于在 ATLL 发展过程中增强信号通路的激活。
