Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
Department of Geriatric Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
Biochem Biophys Res Commun. 2019 May 28;513(2):398-404. doi: 10.1016/j.bbrc.2019.04.001. Epub 2019 Apr 6.
Recent evidence indicated that neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L) has a critical role in the regulation of cellular processes such as apoptosis, transport and metastasis, and is downregulated in several types of cancers. However, the role of NEDD4L in non-small cell lung cancer (NSCLC) has not been fully elucidated. In this study, we demonstrated that NEDD4L was downregulated in NSCLCs. This downregulation correlated with lymph node invasion, advanced stage and poor survival. In vitro experiments revealed that NEDD4L significantly suppressed cell proliferation, migration and invasion abilities. Further in vivo assay demonstrated that knocking down of NEDD4L enhanced the tumor metastasis of NSCLC cells. Moreover, we found that Polycomb group protein enhancer of zeste homologue 2 (EZH2) mediated H3K27 methylation was involved in the downregulation of NEDD4L. Knocking down of EZH2 restored the expression of NEDD4L. Further examined by luciferase reporter assay indicated the EZH2 regulated the transcription activity of NEDD4L. In clinical samples, EZH2 was inversely correlated with NEDD4L expression. In summary, NEDD4L acted as a tumor suppressor gene in NSCLC and targeting EZH2 could upregulate NEDD4L expression, which might serve as a novel approach for NSCLC.
最近的证据表明，发育下调的神经前体细胞表达物 4 样蛋白（NEDD4L）在细胞凋亡、运输和转移等细胞过程的调节中起着关键作用，并且在几种类型的癌症中下调。然而，NEDD4L 在非小细胞肺癌（NSCLC）中的作用尚未完全阐明。在这项研究中，我们证明 NEDD4L 在 NSCLC 中下调。这种下调与淋巴结侵犯、晚期和不良预后相关。体外实验表明，NEDD4L 显著抑制细胞增殖、迁移和侵袭能力。进一步的体内实验表明，敲低 NEDD4L 增强了 NSCLC 细胞的肿瘤转移。此外，我们发现 Polycomb 组蛋白增强子锌指同源物 2（EZH2）介导的 H3K27 甲基化参与了 NEDD4L 的下调。敲低 EZH2 恢复了 NEDD4L 的表达。进一步通过荧光素酶报告基因实验表明，EZH2 调节 NEDD4L 的转录活性。在临床样本中，EZH2 与 NEDD4L 的表达呈负相关。总之，NEDD4L 在 NSCLC 中作为一种肿瘤抑制基因发挥作用，靶向 EZH2 可以上调 NEDD4L 的表达，这可能成为 NSCLC 的一种新方法。
