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

Abstract

Background Circular 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. Methods Quantitative 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. Results The 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. Conclusions Circ_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.

Circ_0076305 facilitates prostate cancer development via sponging miR‐411‐5p and regulating PGK1

“…For instance, circ_0006404, circ_0016068, circ_0057558 and circ‐TRPS1 are all upregulated in PCa and promote PCa development (Ding et al, 2021; Li et al, 2021; Li et al, 2020; Sha et al, 2020). In contrast, circITCH, circ_0004417 and circ_0004296 are all downregulated in PCa and inhibit the progression of PCa (Mao et al, 2021; Wang et al, 2019; Xia et al, 2021). As for circ_0076305, it was upregulated in lung cancer and elevated the cisplatin resistance of lung cancer cells (Dong et al, 2019).…”

Bone marrow mesenchymal stem cells‐derived exosomes mediate nuclear receptor coactivator‐3 expression in osteoblasts by delivering miR‐532‐5p to influence osteonecrosis of the femoral head development

“…Protein expression is assessed by immunofluorescence staining (Mao et al, 2021). In short, the sections were permeabilized with 0.1% Triton‐100, sealed with 5% bovine serum albumin, and then incubated with anti‐cleaved caspase‐3 (9661, Cell Signaling Technology), RUNX2 (ab23981, Abcam).…”

Circular RNAs in and out of Cells: Therapeutic Usages of Circular RNAs

“…While most circular RNAs are localized in the cytoplasm, subsets of circular RNAs are localized in the nucleus ( Zhang et al, 2019 ). Nuclear circular RNAs interact with RNA polymerase II and certain transcription factors to regulate gene expression at the transcriptional level ( Guarnerio et al, 2019 ; Li et al, 2015 ; Zhang et al, 2013 ), whereas some other nuclear circular RNAs affect RNA export and splicing by binding RBPs or forming R-loops with the host gene ( Conn et al, 2017 ; Mao et al, 2021 ; Xu et al, 2020 ) ( Fig. 1B ).…”