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首页> 美国卫生研究院文献>Wiley-Blackwell Online Open >Hypermethylation of the G protein‐coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBPα and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells
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Hypermethylation of the G protein‐coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBPα and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells

机译：G蛋白偶联受体激酶6（GRK6）启动子的超甲基化抑制了C /EBPα的结合而GRK6的敲低促进了肺腺癌细胞中的细胞迁移和侵袭

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We previously reported that the expression of G protein‐coupled receptor kinase 6 (GRK6) is significantly downregulated in lung adenocarcinoma (LADC) tissues, and low expression levels of GRK6 are correlated with poor survival prognosis. However, the specific regulatory mechanisms and functions of GRK6 in LADC remain unknown. Here, we report that GRK6 mRNA expression levels are downregulated in LADC tissues compared to those in matched adjacent non‐tumor tissues (P < 0.001). The promoter of the GRK6 gene was found to be hypermethylated in LADC tissues, and its methylation was correlated with both GRK6 expression and pathology grade. GRK6 promoter hypermethylation may predict shorter overall survival. Treatment with 5‐aza‐2′‐deoxycytidine significantly enhanced GRK6 gene expression. Four binding sites of CCAAT/enhancer‐binding protein‐α (C/EBPα) in the CpG island of the GRK6 gene promoter were predicted in silico, of which three sites were further confirmed by ChIP. Decreased binding of C/EBPα to binding sites 1, 3 and 4 of the GRK6 gene promoter was observed in LADC tissues. Inhibition of C/EBPα significantly inhibited GRK6 expression, while overexpression of C/EBPα significantly promoted GRK6 expression. In addition, overexpression of GRK6 significantly suppressed, while GRK6 knockdown promoted cell migration and invasion. Overexpression of GRK6 enhanced E‐cadherin expression and suppressed vimentin expression, and silencing of GRK6 had the opposite effects. Furthermore, ectopic expression of GRK6 significantly decreased matrix metalloproteinase (MMP) 2 and MMP7 protein expression levels. Our findings suggest that hypermethylation of the GRK6 gene promoter suppressed binding of C/EBPα, thereby contributing to the promotion of cell migration and invasion. The methylation status of the GRK6 promoter might be suitable for use as an epigenetic biomarker, and the C/EBPα–GRK6 signaling pathway may be a potential target for LADC.
机译：我们以前曾报道过，G蛋白偶联受体激酶6（GRK6）的表达在肺腺癌（LADC）组织中显着下调，而低表达的GRK6与不良的生存预后相关。但是，LADC中GRK6的具体调控机制和功能仍然未知。在这里，我们报道与相匹配的相邻非肿瘤组织相比，LADC组织中GRK6 mRNA的表达水平下调（P <0.001）。发现GRK6基因的启动子在LADC组织中被高度甲基化，并且其甲基化与GRK6表达和病理等级相关。 GRK6启动子甲基化可能会预测整体生存期缩短。用5-氮杂-2'-脱氧胞苷处理可显着增强GRK6基因表达。在计算机上预测了GRK6基因启动子的CpG岛中CCAAT /增强子结合蛋白α（C /EBPα）的四个结合位点，其中三个位点已通过ChIP进一步证实。在LADC组织中观察到C /EBPα与GRK6基因启动子的结合位点1、3和4的结合减少。 C /EBPα的抑制显着抑制GRK6表达，而C /EBPα的过表达显着促进GRK6表达。此外，GRK6的过表达显着抑制，而GRK6敲低促进细胞迁移和侵袭。 GRK6的过表达增强E-钙黏着蛋白表达并抑制波形蛋白表达，而GRK6沉默则具有相反的作用。此外，异位表达的GRK6大大降低了基质金属蛋白酶（MMP）2和MMP7蛋白的表达水平。我们的发现表明，GRK6基因启动子的高度甲基化抑制了C /EBPα的结合，从而促进了细胞迁移和侵袭。 GRK6启动子的甲基化状态可能适合用作表观遗传标记，而C / EBPα–GRK6信号通路可能是LADC的潜在靶标。

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