Natural antisense lncRNAs can interfere with their corresponding sense transcript to elicit concordant or discordant regulation.
LncRNA ZNF667-AS1 and its sense gene ZNF667 were found to be downregulated in
esophageal squamous cell carcinoma (ESCC) tissues by
RNA sequencing; however, the exact roles of both genes in ESCC occurrence and development have not been clarified. This study was to investigate the expression patterns, epigenetic inactivation mechanisms, function, and prognostic significance of ZNF667-AS1 and ZNF667 in ESCC
tumorigenesis. Frequent downregulation of ZNF667-AS1 and ZNF667 was detected in
esophageal cancer cells and ESCC tissues. The expression levels of ZNF667-AS1 and ZNF667 were significantly reversed by treatment with 5-Aza-dC and
TSA in
esophageal cancer cell lines. The CpG sites hypermethylation within proximal promoter influenced the binding ability of
transcription factor E2F1 to the binding sites and then affected the transcription and expression of ZNF667-AS1 and ZNF667. Overexpression of ZNF667-AS1 and ZNF667 suppressed the viability, migration, and invasion of
esophageal cancer cells in vitro. Overexpression of ZNF667-AS1 increased
mRNA and
protein expression level of ZNF667. ZNF667-AS1 interacts with and recruits TET1 to its target gene ZNF667 and
E-cadherin to hydrolyze 5'-mc to 5'-hmc and further activates their expression, meanwhile, ZNF667-AS1 also interacts with UTX to decrease
histone H3K27 tri-methylation to activate ZNF667 and
E-cadherin expression. Furthermore, ZNF667-AS1 or ZNF667 expression and promoter methylation status were correlated with ESCC patients' survival. Thus, these findings suggest that ZNF667-AS1 and ZNF667 may act as
tumor suppressors and may serve as potential targets for antitumor
therapy.