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CircVAMP3 Drives CAPRIN1 Phase Separation and Inhibits Hepatocellular Carcinoma by Suppressing c-Myc Translation.

ABSTRACT: Previous studies have identified the regulatory roles of circular RNAs (circRNAs) in human cancers. However, the molecular mechanisms of circRNAs in hepatocellular carcinoma (HCC) remain largely unknown. This study screens the expression profile of circRNAs in HCC and identifies circVAMP3 as a significantly downregulated circRNA in HCC tissues. HCC patients with low circVAMP3 expression present poor prognosis. circVAMP3 negatively regulates the proliferation and metastasis of HCC cells in vitro and in vivo by driving phase separation of CAPRIN1 and promoting stress granule formation in cells, which can downregulate the protein level of Myc proto-oncogene protein by inhibiting c-Myc translation. Furthermore, circVAMP3 is widely expressed in many human tissues and is downregulated in related cancers. Therefore, circVAMP3 is a potential prognostic indicator for HCC and may serve as a therapeutic target for HCC treatment.

SUBMITTER: Chen S

PROVIDER: S-EPMC8922094 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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circVAMP3 Drives CAPRIN1 Phase Separation and Inhibits Hepatocellular Carcinoma by Suppressing c-Myc Translation.

Chen Shuai S Cao Xiaofei X Zhang Jinyang J Wu Wanying W Zhang Bing B Zhao Fangqing F

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220124 8

Previous studies have identified the regulatory roles of circular RNAs (circRNAs) in human cancers. However, the molecular mechanisms of circRNAs in hepatocellular carcinoma (HCC) remain largely unknown. This study screens the expression profile of circRNAs in HCC and identifies circVAMP3 as a significantly downregulated circRNA in HCC tissues. HCC patients with low circVAMP3 expression present poor prognosis. circVAMP3 negatively regulates the proliferation and metastasis of HCC cells in vitro ...[more]

PMID: 35072355

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Project description:BackgroundHepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism.MethodsThe differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR.ResultsLncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues.ConclusionLncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.

Project description:Constitutive heterochromatin is an important component of eukaryotic genomes that has essential roles in nuclear architecture, DNA repair and genome stability, and silencing of transposon and gene expression. Heterochromatin is highly enriched for repetitive sequences, and is defined epigenetically by methylation of histone H3 at lysine 9 and recruitment of its binding partner heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing is that these and associated factors lead to chromatin compaction, resulting in steric exclusion of regulatory proteins such as RNA polymerase from the underlying DNA. However, compaction alone does not account for the formation of distinct, multi-chromosomal, membrane-less heterochromatin domains within the nucleus, fast diffusion of proteins inside the domain, and other dynamic features of heterochromatin. Here we present data that support an alternative hypothesis: that the formation of heterochromatin domains is mediated by phase separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear, cytoplasmic and extracellular compartments. We show that Drosophila HP1a protein undergoes liquid-liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase-separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement and inert probe exclusion at the domain boundary. We conclude that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments. We propose that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviours of heterochromatin, and how chromatin domains in general regulate essential nuclear functions.

Dataset Information

CircVAMP3 Drives CAPRIN1 Phase Separation and Inhibits Hepatocellular Carcinoma by Suppressing c-Myc Translation.

Publications

circVAMP3 Drives CAPRIN1 Phase Separation and Inhibits Hepatocellular Carcinoma by Suppressing c-Myc Translation.

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