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Circular RNA circ-ADD3 inhibits hepatocellular carcinoma metastasis through facilitating EZH2 degradation via CDK1-mediated ubiquitination.

ABSTRACT: Emerging evidence suggests that circular RNA (circRNA) plays a fundamental role in tumorigenesis. However, its contribution to hepatocellular carcinoma (HCC) malignancy remains largely unknown. Here, we performed circRNA microarray expression profile in four paired HCC and normal tissues, and found that circ-ADD3, a novel circRNA derived from linear ADD3 exon 4 to exon 12, was significantly downregulated in HCC, which was further validated in 112 matched HCC and paracancerous tissues. High circ-ADD3 expression was negatively correlated with vascular invasion, intrahepatic metastasis as well as distant metastasis. Moreover, it was identified as an effective biomarker for diagnosis and prognosis of HCC. Functionally, exogenous expression of circ-ADD3 dramatically weakened HCC cell invasion and metastasis both in vitro and in vivo. Mechanistically, circ-ADD3 was capable of reinforcing the interaction between CDK1 and EZH2, resulting in increased EZH2 ubiquitination and subsequent degradation via phosphorylation at Thr-345 and Thr-487 sites. The decreased EZH2 markedly increased the expression of a cohort of anti-metastatic genes, including circ-ADD3, by reducing H3K27me3 levels on their promoter regions, which formed a regulatory circuit, thereby dampening HCC metastasis. Taken together, our findings unveil the essential role of circ-ADD3 in inhibiting HCC metastasis through regulation of EZH2 stability.

SUBMITTER: Sun S

PROVIDER: S-EPMC6726993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveCirc-centro-some/spindle pole-associated protein (CSPP1) has been confirmed to be characterized in diverse human malignancies and its ectopic expression may regulate tumor progression and development. However, in hepatocellular carcinoma (HCC), its biological role, clinical significance and molecular mechanism are still unclear.MethodsCirc-CSPP1 expression and its prognostic values in HCC tissues were detected by qRT-PCR or in situ hybridization (ISH), and enriched by using Rnase R. The functional experiments (Circ-CSPP1 was overexpressed or knocked down) were performed in HCC cells. The HCC cell growth was analyzed by CCK-8 assay, transwell, wound healing and colony formation assays. The interation between circ-CSPP1 and miR-577/miR-577 and cyclin E2 (CCNE2) were determined by dual luciferase assay or RNA binding protein immunoprecipitation (RIP) assay. The RNA fluorescence in situ hybridization (FISH) assay was used to detect the subcellular distribution. Finally, an in vivo nude mouse tumor model was constructed.ResultsIn HCC patients and cells, circ-CSPP1 was aberrantly expressed, and its upregulation predicted poor prognosis, and closely correlated with tumor size and TNM stage. Circ-CSPP1 resisted RnaseR digestion, indicating it is a circular RNA structure. Moreover, overexpression of circ-CSPP1 promoted HCC cell viability, colony formation, migration, and invasion in vitro. Knockdown of circ-CSPP1 showed contrary results. Circ-CSPP1 acts as a miR-577 sponge and positively regulated the target of miR-577, CCNE2. Besides, miR-577 inhibitor rescued the suppressive effects of circ-CSPP1 knockdown on HCC cell growth, whereas was completely reversed by silencing of CCNE2. Finally, the in vivo experiments confirmed that circ-CSPP1 knockdown regulated xenograft tumor volume and downregulated CCNE2, p-Rb, E2F1 and c-myc expression.ConclusionThese findings revealed that circ-CSPP1 contributed to HCC progression by positively regulating CCNE2 via miR-577, thus established its potential as new a prognostic and therapeutic marker for HCC patients.

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Circular RNA circ-ADD3 inhibits hepatocellular carcinoma metastasis through facilitating EZH2 degradation via CDK1-mediated ubiquitination.

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