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PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay.

ABSTRACT: Glioblastoma is the most common and malignant form of primary central nervous tumor in adults. Long noncoding RNAs (lncRNAs) have been reported to play a pivotal role in modulating gene expression and regulating human tumor's malignant behaviors. In this study, we confirmed that lncRNA brain-derived neurotrophic factor antisense (BDNF-AS) was downregulated in glioblastoma tissues and cells, interacted and stabilized by polyadenylate-binding protein cytoplasmic 1 (PABPC1). Overexpression of BDNF-AS inhibited the proliferation, migration, and invasion, as well as induced the apoptosis of glioblastoma cells. In the in vivo study, PABPC1 overexpression combined with BDNF-AS overexpression produced the smallest tumor and the longest survival. Moreover, BDNF-AS could elicit retina and anterior neural fold homeobox 2 (RAX2) mRNA decay through STAU1-mediated decay (SMD), and thereby regulated the malignant behaviors glioblastoma cells. Knockdown of RAX2 produced tumor-suppressive function in glioblastoma cells and increased the expression of discs large homolog 5 (DLG5), leading to the activation of the Hippo pathway. In general, this study elucidated that the PABPC1-BDNF-AS-RAX2-DLG5 mechanism may contribute to the anticancer potential of glioma cells and may provide potential therapeutic targets for human glioma.

SUBMITTER: Su R

PROVIDER: S-EPMC6997171 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay.

Su Rui R Ma Jun J Zheng Jian J Liu Xiaobai X Liu Yunhui Y Ruan Xuelei X Shen Shuyuan S Yang Chunqing C Wang Di D Cai Heng H Li Zhen Z Xue Yixue Y

Cell death & disease 20200203 2

Glioblastoma is the most common and malignant form of primary central nervous tumor in adults. Long noncoding RNAs (lncRNAs) have been reported to play a pivotal role in modulating gene expression and regulating human tumor's malignant behaviors. In this study, we confirmed that lncRNA brain-derived neurotrophic factor antisense (BDNF-AS) was downregulated in glioblastoma tissues and cells, interacted and stabilized by polyadenylate-binding protein cytoplasmic 1 (PABPC1). Overexpression of BDNF- ...[more]

PMID: 32015336

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Project description:BackgroundFerroptosis is a novel form of iron-dependent cell death and participates in the malignant progression of glioblastoma (GBM). Although circular RNAs (circRNAs) are found to play key roles in ferroptosis via several mechanisms, including regulating iron metabolism, glutathione metabolism, lipid peroxidation and mitochondrial-related proteins, there are many novel circRNAs regulating ferroptosis need to be found, and they may become a new molecular treatment target in GBM.MethodsThe expression levels of circLRFN5, PRRX2 and GCH1 were detected by qPCR, western blotting, and immunohistochemistry. Lentiviral-based infections were used to overexpress or knockdown these molecules in glioma stem cells (GSCs). The biological functions of these molecules on GSCs were detected by MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), the 5-ethynyl-20-deoxyuridine (EdU) incorporation assay, transwell, neurosphere formation assays, Extreme Limiting Dilution Analysis (ELDA) and xenograft experiments. The content of ferroptosis levels in GSCs was detected by BODIPY 581/591 C11 assay, glutathione (GSH) assay and malondialdehyde (MDA) assay. The regulating mechanisms among these molecules were studied by RNA immunoprecipitation assay, RNA pull-down assay, ubiquitination assay, dual-luciferase reporter assay and chromatin immunoprecipitation assay.ResultsWe found a novel circRNA circLRFN5 is downregulated in GBM and associated with GBM patients' poor prognosis. CircLRFN5 overexpression inhibits the cell viabilities, proliferation, neurospheres formation, stemness and tumorigenesis of GSCs via inducing ferroptosis. Mechanistically, circLRFN5 binds to PRRX2 protein and promotes its degradation via a ubiquitin-mediated proteasomal pathway. PRRX2 can transcriptionally upregulate GCH1 expression in GSCs, which is a ferroptosis suppressor via generating the antioxidant tetrahydrobiopterin (BH4).ConclusionsOur study found circLRFN5 as a tumor-suppressive circRNA and identified its role in the progression of ferroptosis and GBM. CircLRFN5 can be used as a potential GBM biomarker and become a target for molecular therapies or ferroptosis-dependent therapy in GBM.

Project description:BackgroundSevoflurane (Sev), a commonly used volatile anesthetic, has been reported to inhibit the process of colorectal cancer (CRC). Circular RNAs (circRNAs) are revealed to participate in the pathogenesis of CRC. This study aims to reveal the mechanism of hsa_circ_0000231 in Sev-mediated CRC progression.MethodsThe expression of hsa_circ_0000231 and microRNA-622 (miR-622) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein level was determined by western blot analysis. Cell proliferation was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell colony formation and DNA content quantitation assays. Cell apoptosis was detected by Annexin V-fluorescein isothiocyanate and propidium iodide double staining and caspase 3 activity assays. Cell migration and invasion were investigated by wound-healing and transwell invasion assays, respectively. The putative relationship between hsa_circ_0000231 and miR-622 was predicted by circular RNA Interactome online database, and identified by dual-luciferase reporter and RNA immunoprecipitation assays. The impacts of hsa_circ_0000231 on Sev-mediated tumor formation in vivo were presented by in vivo assay.ResultsHsa_circ_0000231 expression was upregulated, while miR-622 was downregulated in CRC tissues and cells compared with control groups. Sev treatment decreased hsa_circ_0000231 expression, but increased miR-622 expression in CRC cells. Sev treatment suppressed cell proliferation, migration and invasion, and induced cell apoptosis. Hsa_circ_0000231 overexpression restored Sev-mediated CRC progression in vitro. Additionally, hsa_circ_0000231 acted as a sponge of miR-622, and miR-622 inhibitors reversed the impacts of hsa_circ_0000231 silencing on CRC process. Furthermore, Sev treatment inhibited tumor growth by regulating hsa_circ_0000231 in vivo.ConclusionHsa_circ_0000231 attenuated Sev-aroused repression impacts on CRC development by sponging miR-622. This findings may provide an appropriate anesthetic protocol for CRC sufferers undergoing surgery.

Dataset Information

PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay.

Publications

PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay.

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