The coordination between ZNF217 and LSD1 contributes to hepatocellular carcinoma progress and is negatively regulated by miR-101

Abstract

Zinc-figure protein 217 (ZNF217) is a C2H2 zinc finger transcription factor that works as a pivotal effector stimulating embryonic immortalization as well as oncogenicity during multiple cancer processes. Nevertheless, the expression of ZNF217 in hepatocellular carcinoma (HCC) and the underlying specific molecular mechanisms remains elusive. In the present study, we aimed to explore the potential role of ZNF217 in HCC cell proliferation and invasion, as well as the underlying mechanism. Here, we demonstrated that the expression of ZNF217 was higher in HCC patients and indicated worse overall survival times, which was confirmed by Oncomine datasets and The Cancer Genome Atlas (TCGA) HCC cohorts. Further research discovered that knockdown of ZNF217 inhibited the proliferation of HCC cells in vitro and in vivo. Enforced expression of ZNF217 could promote Epithelial-mesenchymal transition and thus the invasion of HCC cells. Mechanistically, we identified ZNF217 interacted with LSD1 in vivo and in vitro. Knockdown of ZNF217 was accompanied by a parallel increase in di-methyl histone 3 lysine4 levels on CDH1 promoter, which indicated ZNF217 could recruit LSD1 to affect CDH1 epigenetic expression from transcription level. Of note, bioinformatics analyses, a dual luciferase reporter assay, RT-qPCR and western blot analysis demonstrated that microRNA-101 (miR-101), a well-known tumor suppressor in HCC, acted as a negative regulator of ZNF217. The inhibition of HCC progression by miR-101 was counteracted by ZNF217 overexpression. Taken together, our study presents the regulation mechanism of miR-101/ZNF217/CDH1 axis for the first time and provides new evidences of ZNF217 as a potential therapeutic target for HCC patients.