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. (C) 2019 Published by Elsevier Inc.