ZNF582 hypermethylation promotes metastasis of nasopharyngeal carcinoma by regulating the transcription of adhesion molecules Nectin‐3 and NRXN3

Abstract

Background Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC). However, the epigenetic mechanisms underlying NPC metastasis remains poorly understood. We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment. Methods Bisulfite pyrosequencing was used to analyze zinc finger protein 582 (ZNF582) methylation in NPC tissues and cell lines. Quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and Western blotting were used to determine the expression of ZNF582. In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC. ZNF582‐targeting genes were identified by chromatin immunoprecipitation sequencing (ChIP‐seq) and were confirmed by ChIP‐qPCR and luciferase assay. Results ZNF582 promoter was hypermethylated in NPC, and both the mRNA and protein levels of ZNF582 were down‐regulated in NPC tissues and cell lines. The restoration of ZNF582 inhibited NPC migration, invasion, and metastasis, while the knockdown of ZNF582 promoted NPC migration, invasion, and metastasis in vitro and in vivo. ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin‐3 and NRXN3. Both Nectin‐3 and NRXN3 were identified as functional targets of ZNF582, and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis. Conclusions ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin‐3 and NRXN3, which may provide novel therapeutic targets for NPC treatment.

Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

“…Epstein–Barr virus (EBV), a large double-stranded DNA virus belonging to the γ-herpesvirus subfamily, causes latent infection of more than 95% of the adult population worldwide ( 1 , 2 ). As a widespread virus causing infectious mononucleosis during primary infection, EBV is also closely implicated in several malignancies in latent infection, including B-cell lymphomas, nasopharyngeal carcinoma (NPC) ( 3 , 4 , 5 ), EBV-associated gastric cancer, Burkitt's lymphoma, and Hodgkin's lymphoma ( 6 , 7 , 8 , 9 ). The viral oncogenic factors, such as RNA transcripts and proteins expressing during the latent or lytic phase have been reported to drive pathogenic processes ( 10 , 11 ).…”

Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma

“…Surprisingly, no DMCs were found in TP53. Among DMCcorrelated TF genes, some have been implicated in the progression of ESCC, including zinc finger genes such as ZNF382, ZNF582 and ZNF667 28,30,31 and Homeobox genes such as BARX1, HOXA13 and HOXC10. [32][33][34] All 7 CpG sites at the promoter of ZNF382, a NF-κB inhibitor frequently downregulated in ESCC, 28,35 were recurrently hyper-methylated in our data: at least one of the 7 DMCs were found in 75.82% (69/91) ESCC genomes.…”

Current Insights into Oral Cancer Diagnostics

“…A recent report has revealed that ZNF582 acts as a tumor suppressor gene in nasopharyngeal carcinoma (NPC) by regulating the transcription and expression of the adhesion molecules Nectin-3 and NRXN3 . Hypermethylation of ZNF582 promotes NPC metastasis via the regulation of these adhesion molecules [ 67 ]. The tumor suppressor role of ZNF582 was also observed in anal cancer and esophageal carcinoma, and its methylation seems to have potential as a cancer detection biomarker [ 68 , 69 ].…”