Abstract
Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.
Highlights
Hepatocellular carcinoma (HCC) is malignant liver cancer, which accounts for the fourth major cause of cancer-related deaths in less developed regions according to GLOBOCAN 20121
The expression profiling of Long noncoding RNAs (lncRNAs) and mRNA on GSE115018 were downloaded from the Gene Expression Omnibus, in which a significant difference between the expression of lncRNAs and mRNAs in HCC and that of the adjacent control was discovered by microarray analysis (P < 0.05 and |log2FC| > 1)
The top 20 differentially expressed mRNAs (Fig. 1a) and the top 30 differentially expressed lncRNAs (Fig. 1b) were demonstrated using heatmap, in which both CDK4 and SNHG1 were upregulated in HCC group in comparison with the control group
Summary
Hepatocellular carcinoma (HCC) is malignant liver cancer, which accounts for the fourth major cause of cancer-related deaths in less developed regions according to GLOBOCAN 20121. Antiviral drugs were used for HBV and HCV treatment, Long noncoding RNAs (lncRNAs) are RNA transcripts with over 200 nucleotides in length but do not code proteins[3]. Accumulating studies have revealed that the transcription and posttranscriptional controls exerted by lncRNAs play an important role in the biological development of various cancers including lung cancer and HCC4,5. A study found that SNHG1 was found to be upregulated in non-small cell lung cancer and the overexpression promoted cell proliferation[5]. Previous clinical research defined SNHG1 as a carcinogenic gene in HCC, which stimulates cell proliferation, promotes the course of Official journal of the Cell Death Differentiation Association
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