Aberrant hypermethylation-mediated downregulation of antisense lncRNA ZNF667-AS1 and its sense gene ZNF667 correlate with progression and prognosis of esophageal squamous cell carcinoma
Aberrant hypermethylation-mediated downregulation of antisense lncRNA ZNF667-AS1 and its sense gene ZNF667 correlate with progression and prognosis of esophageal squamous cell carcinoma
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异常高甲基化介导的反义lncRNA ZNF667-AS1及其正义基因ZNF667的下调与食管鳞状细胞癌的进展和预后相关
DOI：
10.1038/s41419-019-2171-3
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发表时间：
2019-12-05
影响因子：
9
通讯作者：
Guo, Wei
中科院分区：
文献类型：
--
作者：
Dong, Zhiming;Li, Shengmian;Guo, Wei
天然反义lncRNA可以干扰其相应的有义转录物以引起一致或不一致的调节。RNA测序发现ZNF 667-AS 1及其正义基因ZNF 667在食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）组织中表达下调，但这两个基因在ESCC发生发展中的确切作用尚不清楚。本研究旨在探讨ZNF 667-AS 1和ZNF 667在食管鳞癌中的表达模式、表观遗传失活机制、功能及预后意义。ZNF 667-AS 1和ZNF 667在食管癌细胞和食管鳞癌组织中表达下调。5-Aza-dC和TSA处理食管癌细胞株后，ZNF 667-AS 1和ZNF 667的表达水平明显逆转。ZNF 667-AS 1和ZNF 667基因启动子近端CpG位点的甲基化影响转录因子E2 F1与该结合位点的结合能力，进而影响ZNF 667-AS 1和ZNF 667的转录和表达。ZNF 667-AS 1和ZNF 667过表达抑制食管癌细胞的存活、迁移和侵袭。过表达ZNF 667-AS 1可提高ZNF 667的mRNA和蛋白表达水平。ZNF 667-AS 1与TET 1相互作用，将TET 1募集到靶基因ZNF 667和E-cadherin上，使5′-mc水解为5′-hmc，进而激活其表达;同时，ZNF 667-AS 1还与UTX相互作用，降低组蛋白H3 K27三甲基化，从而激活ZNF 667和E-cadherin的表达。此外，ZNF 667-AS 1或ZNF 667表达和启动子甲基化状态与ESCC患者的生存相关。因此，这些发现表明ZNF 667-AS 1和ZNF 667可能作为肿瘤抑制剂，并可能作为抗肿瘤治疗的潜在靶点。
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.