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UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs.

ABSTRACT: Glioblastoma multiforme (GBM) is the most lethal type of craniocerebral gliomas. Glioma stem cells (GSCs) are fundamental reasons for the malignancy and recurrence of GBM. Revealing the critical mechanism within GSCs' self-renewal ability is essential. Our study found a novel circular RNA (circRPPH1) that was up-regulated in GSCs and correlated with poor survival. The effect of circRPPH1 on the malignant phenotype and self-renewal of GSCs was detected in vitro and in vivo. Mechanistically, UPF1 can bind to circRPPH1 and maintain its stability. Therefore, more existing circRPPH1 can interact with transcription factor ATF3 to further transcribe UPF1 and Nestin expression. It formed a feedback loop to keep a stable stream for stemness biomarker Nestin to strengthen tumorigenesis of GSCs continually. Besides, ATF3 can activate the TGF-β signaling to drive GSCs for tumorigenesis. Knocking down the expression of circRPPH1 significantly inhibited the proliferation and clonogenicity of GSCs both in vitro and in vivo. The overexpression of circRPPH1 enhanced the self-renewal of GSCs. Our findings suggest that UPF1/circRPPH1/ATF3 maintains the potential self-renewal of GSCs through interacting with RNA-binding protein and activating the TGF-β signal pathway. Breaking the feedback loop against self-renewing GSCs may represent a novel therapeutic target in GBM treatment.

SUBMITTER: Xu J

PROVIDER: S-EPMC9308777 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs.

Xu Jinkun J Zhang Guoqing G Hu Jinpeng J Li Hao H Zhao Junshuang J Zong Shengliang S Guo Zhengting Z Jiang Yang Y Jing Zhitao Z

Cell death & disease 20220723 7

Glioblastoma multiforme (GBM) is the most lethal type of craniocerebral gliomas. Glioma stem cells (GSCs) are fundamental reasons for the malignancy and recurrence of GBM. Revealing the critical mechanism within GSCs' self-renewal ability is essential. Our study found a novel circular RNA (circRPPH1) that was up-regulated in GSCs and correlated with poor survival. The effect of circRPPH1 on the malignant phenotype and self-renewal of GSCs was detected in vitro and in vivo. Mechanistically, UPF1 ...[more]

PMID: 35871061

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Project description:BackgroundGlioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified.MethodsThe highly enriched circRNAs in glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression of circRNF10 in glioma and normal brain tissue. Both gain-of-function and loss-of-function studies were used to assess the effects of circRNF10 on ferroptosis using in vitro and in vivo assays. The hypothesis that ZBTB48 promotes ferroptosis defense was established using bioinformatics analysis and functional assays. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between circRNF10 and target proteins including ZBTB48, MKRN3 and IGF2BP3. The posttranslational modification mechanism of ZBTB48 was verified using coimmunoprecipitation (co-IP) and ubiquitination assays. The transcription activation of HSPB1 and IGF2BP3 by ZBTB48 was confirmed through luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The stabilizing effect of IGF2BP3 on circRNF10 was explored by actinomycin D assay. Finally, a series of in vivo experiments were performed to explore the influences of circRNF10 on the glioma progression.ResultsA novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated in glioblastoma tissues and correlated with patients' poor prognosis. Through integrated analysis of the circRNA-proteins interaction datasets and sequencing results, we reveal ZBTB48 as a transcriptional factor binding with circRNF10, notably promoting upregulation of HSPB1 and IGF2BP3 expression to remodel iron metabolism and facilitates the launch of a circRNF10/ZBTB48/IGF2BP3 positive feedback loop in GSCs. Additionally, circRNF10 can competitively bind to MKRN3 and block E3 ubiquitin ligase activity to enhance ZBTB48 expression. Consequently, circRNF10-overexpressed glioma stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors for ferroptosis evading.ConclusionOur research presents abnormal circRNAs expression causing a molecular and metabolic change of glioma, which we leverage to discover a therapeutically exploitable vulnerability to target ferroptosis.

Dataset Information

UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs.

Publications

UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs.

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