Department of Clinical Nutrition, Jinhua Municipal Central Hospital, Jinhua, China.
Department of Health Education and Administration, Jinhua Municipal Central Hospital, Jinhua, China.
J Cell Physiol. 2019 Aug;234(10):19010-19018. doi: 10.1002/jcp.28540. Epub 2019 Mar 25.
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene, a widely known cancer inhibitor, could effectively suppress cancer metastasis and angiogenesis. Downregulation or loss of RECK expression frequently occurs during cancer progression. However, the mechanism underlying RECK dysregulation has not been fully elucidated. Herein, we reported for the first time that enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could epigenetically attenuate RECK expression via catalyzing H3K27 trimethylation (H3K27me3) within the RECK promoter. Furthermore, we also proved, for the first time, the involvement of EZH2 in the inhibition of RECK by extracellular signal-related kinases (ERK)-1/2 signaling. Next, we revealed that the modulation of the enzymic activity of EZH2 resulting from posttranslational phosphorylation at the serine-21 site was responsible for the increased enrichment of H3K27me3 at the RECK promoter region by ERK1/2 signaling. Collectively, the results of our study shed more light on the mechanisms responsible for the dysregulation of RECK by the ERK1/2 pathway.
富含半胱氨酸的天冬氨酸蛋白水解酶抑制因子（RECK）基因是一种广泛知晓的癌症抑制剂，能够有效抑制癌症转移和血管生成。在癌症进展过程中，RECK 的表达常常下调或缺失。然而，RECK 失调的机制尚未完全阐明。在此，我们首次报道组蛋白甲基转移酶增强子结合锌指蛋白 2（EZH2）可通过催化 RECK 启动子内的 H3K27 三甲基化（H3K27me3）来表观遗传地下调 RECK 的表达。此外，我们还首次证明了细胞外信号相关激酶（ERK）-1/2 信号通路参与了 EZH2 对 RECK 的抑制作用。接下来，我们揭示了丝氨酸 21 位点的翻译后磷酸化导致 EZH2 酶活性的调节，这是 ERK1/2 信号通路导致 RECK 启动子区域 H3K27me3 富集增加的原因。总的来说，我们的研究结果更深入地阐明了 ERK1/2 通路导致 RECK 失调的机制。
