Abstract
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.
Highlights
Esophageal cancer is the ninth most common cancer in the world, and the sixth most common cause of cancer-Official journal of the Cell Death Differentiation AssociationDong et al Cell Death and Disease (2019)10:930Family aggregation occurs in these high-risk areas; the exact etiology and mechanisms of esophageal squamous cell carcinoma (ESCC) remain unclear.Long noncoding RNAs, which often lack protein-coding capabilities, have recently been investigated as oncogenes or tumor suppressors by regulating many biological processes in human cancers via diverse mechanisms[5,6]
ZNF667-AS1 was first reported in a study using microarray analysis to analyze the changed genes in immortalized human mammary epithelial cells (HMEC), and ZNF667-AS1 was found to be expressed in all normal finite lifespan human cells examined to date, and was downregulated or inactivated in immortalized HMEC11
Analysis of The Cancer Genome Atlas (TCGA) data across 16 human cancers revealed that deregulation of ZNF667-AS1 expression due to DNA hypermethylation was a frequent event in most common human cancers[11]
Summary
Esophageal cancer is the ninth most common cancer in the world, and the sixth most common cause of cancer-Official journal of the Cell Death Differentiation AssociationDong et al Cell Death and Disease (2019)10:930Family aggregation occurs in these high-risk areas; the exact etiology and mechanisms of ESCC remain unclear.Long noncoding RNAs (lncRNAs), which often lack protein-coding capabilities, have recently been investigated as oncogenes or tumor suppressors by regulating many biological processes in human cancers via diverse mechanisms[5,6]. Official journal of the Cell Death Differentiation Association. Dong et al Cell Death and Disease (2019)10:930. Aggregation occurs in these high-risk areas; the exact etiology and mechanisms of ESCC remain unclear. Long noncoding RNAs (lncRNAs), which often lack protein-coding capabilities, have recently been investigated as oncogenes or tumor suppressors by regulating many biological processes in human cancers via diverse mechanisms[5,6]. NATs are transcribed in the opposite direction to protein-coding transcripts, and are widespread in eukaryotes[7]. Despite being processed mostly from protein-coding loci, they frequently display distinct characteristics compared with their sense partners[8]. NATs may be expressed at lower levels than sense transcripts and often demonstrate high tissue specificity. The exact molecular mechanisms triggered by NATs in the context of these regulatory roles are currently poorly understood
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