Hsa_circ_0004296 inhibits metastasis of prostate cancer by interacting with EIF4A3 to prevent nuclear export of ETS1 mRNA

Shiyu Mao,Yadong Guo,Yang Yan,Hong Wang,Junfeng Zhang,Wenchao Ma,Fuhan Yang,Ruiliang Wang,Wentao Zhang,Cheng Li,Yuan Wu,Xudong Yao,Zongtai Zheng,Niraj Maskey

doi:10.1186/s13046-021-02138-8

Abstract

BackgroundCircular RNAs (circRNAs) have been shown to play vital biological functions in various tumors, including prostate cancer (PCa). However, the roles of circRNAs in the metastasis of PCa remain unclear. In the present study, differentially expressed circRNAs associated with PCa metastasis were screened using high-throughput RNA sequencing, from which hsa_circ_0004296 was identified.MethodsQuantitative real-time PCR (qRT-PCR) was used to detect the expression of circ_0004296 in PCa tissues and adjacent normal tissues as well as in blood and urine. Gain and loss of function experiments were performed to investigate the function of circ_0004296 in PCa. Bioinformatics analyses, RNA pull-down assay, and mass spectrometry were conducted to identify RNA-binding proteins. RNA immunoprecipitation and RNA and protein nuclear-cytoplasmic fractionation were performed to investigate the underlying mechanism. A xenograft mouse model was used to analyze the effect of circ_0004296 on PCa growth and metastasis in vivo.ResultsThe expression of circ_0004296 was decreased in PCa tissues, blood, and urine, which was negatively associated with metastasis. Furthermore, gain and loss of function experiments in vitro and in vivo showed that circ_0004296 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of PCa cells. Mechanistically, circ_0004296 regulated host gene ETS1 expression at the post-transcriptional level. EIF4A3 was identified and confirmed as the downstream binding protein of circ_0004296. EIF4A3 expression was significantly upregulated in PCa tissues and associated with PCa metastasis. Silencing EIF4A3 suppressed PCa cell proliferation, migration, invasion, and EMT.ConclusionsCirc_0004296 overexpression efficiently inhibited ETS1 mRNA nuclear export by promoting EIF4A3 retention in the nucleus, leading to the downregulation of ETS1 expression and suppression of PCa metastasis; thus, circ_0004296 might be a potential biomarker and therapeutic target for patients with PCa.

Highlights

Circular RNAs have been shown to play vital biological functions in various tumors, including prostate cancer (PCa)
Whole‐transcriptome sequencing (RNA‐seq) Five pairs of PCa tissues and matched local metastatic lymph node tissues were used for RNA-seq
Circ_0004296 is negatively associated with PCa metastasis To investigate whether Circular RNA (circRNA) are involved in PCa metastasis, five pairs of PCa tissues and matched local metastatic lymph node tissues were used for RNA-seq

Summary

Introduction

Circular RNAs (circRNAs) have been shown to play vital biological functions in various tumors, including prostate cancer (PCa). The roles of circRNAs in the metastasis of PCa remain unclear. Differentially expressed circRNAs associated with PCa metastasis were screened using high-throughput RNA sequencing, from which hsa_circ_0004296 was identified. CircRNAs play potentially important roles in tumorigenesis and tumor progression through competitive endogenous RNAs (ceRNAs), encoded proteins, interaction with proteins, and modulation of transcription [10,11,12,13]. Recent emerging evidence suggests that circRNAs plays important roles in PCa, with the findings indicating their involvement in tumor cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) [14, 15]. The functions and mechanisms of most circRNAs remain largely unexplored in PCa metastasis

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Discussion

Conclusion