Circular RNAs negatively regulate cancer stem cells by physically binding FMRP against CCAR1 complex in hepatocellular carcinoma

Abstract

Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. It has been reported playing roles in multiple malignant behaviors including proliferation, migration, metastasis and chemoresistance. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported yet. Methods: circZKSCAN1 level was detected in HCC tissue microarrays to clarify its prognostic values. Gain and loss function experiments were applied to investigate the role of circZKSCAN1 in HCC stemness. Bioinformatic analysis was used to predict the possible downstream RNA binding protein and further RNA immunoprecipitation sequencing was carried out to identify the RBP-regulated genes. Results: The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and β-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restrain the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1. Conclusion: Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5-circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.

The Circular RNA circZFR Phosphorylates Rb Promoting Cervical Cancer Progression by Regulating the SSBP1/CDK2/cyclin E1 Complex

“…CircRHOT1 was found to promote hepatocellular carcinoma (HCC) growth through the recruitment of TIP60 to the promoter of NR2F6 and initiating NR2F6 transcription [49]. A study reported that circZKSCAN1 physically bound an RBP FMRP against CCAR1 complex and inhibited HCC [50]. Circ-Foxo3 was found to bind both cyclin-dependent kinase (CDK) 2 and a known CDK-inhibitor p21.…”

Profiles of prognostic alternative splicing signature in hepatocellular carcinoma

“…29,30 In our study, we identified 12 splicing factors that were abnormally expressed in HCC. Previous studies identified splicing factors associated with HCC, such as PFS, 31 FMRP, 32 YB-1, 33,34 hnRNPH1, 35 and SRp20. 36,37 However, these studies did not perform functional analyses.…”

Functional roles of circular RNAs during epithelial-to-mesenchymal transition

“…Yanjie Wang et al demonstrated that circRNA_ 014511 could affect the expression of P53, regulate cell apoptosis and cell cycle arrest, and influence the radiosensitivity of bone marrow mesenchymal stem cells (BMMCs) by adsorbing miR-29b-2-5p. Furthermore, Yan-Jing Zhu et al found that circZKSCAN1 suppressed cell stemness in HCC by regulating the function of the RBP fragile X mental retardation protein (FMRP), whose downstream target gene is cell cycle and apoptosis regulator 1 (CCAR1) and showed that CCAR1 acts as a coactivator of the Wnt/β-catenin signaling pathway and upregulates cell stemness [134].…”