Abstract
Long non-coding RNAs (lncRNAs), some of the most abundant epigenetic regulators, play an important role in esophageal squamous cell carcinoma (ESCC). In the current study, the functions and mechanisms of the lncRNA LINC00673 were investigated. The expression levels of LINC00673 and its potential target genes were assessed by quantitative real-time polymerase chain reaction (qPCR) in ESCC surgical specimens and ESCC cell lines. RNA fluorescence in situ hybridization (RNA FISH) was employed to detect the subcellular location and the levels of LINC00673 in ESCC samples from patients with different survival times. LINC00673 function in ESCC carcinogenesis was also evaluated in vivo and in vitro. Cell cycle synchronization was performed using serum withdrawal; the cell cycle was monitored by fluorescence analysis and cellular DNA was detected by flow cytometry. The molecular mechanisms underlying LINC00673 were explored via Western blotting, chromatin immunoprecipitation (ChIP), and ChIP-PCR. Up-regulated LINC00673 was associated with poor prognosis in ESCC patients and promoted the proliferation of ESCC cells both in vitro and in vivo. Compared to the control group, depletion of LINC00673 in ESCC cells arrested the cell cycle, at least, at the G1/S checkpoint. Knockdown of LINC00673 significantly enhanced posttranscriptional expression of CDKN2C, and histone 3 lysine 27 trimethylation (H3K27me3) was enriched at the promoter region of CDKN2C. After inhibiting EZH2, the CDKN2C expression levels were increased. The present findings are the first to reveal that LINC00673 represses CDKN2C expression and promotes ESCC cell proliferation by elevating EZH2-mediated H3K27me3 levels. These data suggest that LINC00673 regulates the cell cycle in ESCC and that it is a promising target for clinical therapy.
Highlights
Esophageal cancer (EC) is one of the most prevalent solid tumor cancers worldwide, ranking seventh, and sixth in morbidity and mortality, respectively (1)
The value of LINC00673 in the diagnosis of esophageal squamous cell carcinoma (ESCC) was measured by a receiver operating characteristic (ROC) curve
Our results demonstrate that LINC00673 is up-regulated in ESCC and can, to some extent, predict poor prognosis
Summary
Esophageal cancer (EC) is one of the most prevalent solid tumor cancers worldwide, ranking seventh, and sixth in morbidity and mortality, respectively (1). The mechanisms underlying human ESCC progression need to be further investigated. LncRNAs are critical regulators of multiple disease processes and may function as oncogenes or tumor suppressors by modulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels (6–9). Compared with other solid tumors with a high incidence, a few studies of lncRNAs in ESCC have been reported; the molecular mechanisms of lncRNAs are intricate, and they have not been fully elucidated. Genomic copy number variations (CNVs) and abnormal expression of genes commonly occur in various tumors, including ESCC. We explored the biological functions and molecular epigenetic mechanisms of LINC00673 in ESCC, and our findings indicate that LINC00673 might be a regulator of CDKN2C through histone methylation modification
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