CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in...

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Published in:Journal of experimental & clinical cancer research 2020-11, Vol.39 (1), p.1-259, Article 259
Main Authors: Zhao, Zhongwei, Song, Jingjing, Tang, Bufu, Fang, Shiji, Zhang, Dengke, Zheng, Liyun, Wu, Fazong, Gao, Yang, Chen, Chunmiao, Hu, Xianghua, Weng, Qiaoyou, Yang, Yang, Tu, Jianfei, Ji, Jiansong
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Apoptosis
Cancer
Cell adhesion & migration
Cell cycle
Cell growth
Cholecystokinin
Chromatin
CRISPR
Deoxyribonucleic acid
Development and progression
DNA
DNA methylation
Epigenetic inheritance
Gene expression
Genes
Genetic aspects
Genetic transcription
Genomes
Genomics
Hepatoma
Liver cancer
Manufacturers
Medical research
Medicine, Experimental
Methylation
Methyltransferases
MicroRNA
Pathogenesis
Proteins
Reagents
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Summary:Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC. Keywords: Hepatocellular carcinoma, Circular RNA, JAK2/STAT3, DNMT3a
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-020-01769-7