Dataset Information

Depletion of the N⁶-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

ABSTRACT: Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed light on an unrecognized regulatory function of IGF2BP3 in ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in ferroptosis.

SUBMITTER: Deng L

PROVIDER: S-EPMC10907351 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Depletion of the N<sup>6</sup>-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Deng Limei L Di Yunbo Y Chen Caiyun C Xia Juan J Lei Bingxi B Li Ning N Zhang Qingyu Q

Cell death & disease 20240301 3

Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by ...[more]

PMID: 38429265

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Project description:BackgroundGlioblastoma (GBM) is a highly aggressive cancer having a dismal prognosis. N6-methyladenosine (m6A) is closely related to GBM progression. The significance of m6A modifications depends on the m6A readers, whose functions in glioma progression are largely unknown. This study sought to investigate the expression of the m6A related gene in glioma and its effect on the malignant progression of glioma.MethodsThe expression differences between low-grade gliomas (LGGs) and high-grade gliomas (HGGs), and among 19 m6A-related genes were analyzed by The Cancer Genome Atlas (TCGA). Survival probability was analyzed in terms of the high or low expression of insulin growth factor-2 binding protein 3 (IGF2BP3) in the TCGA data set. The clinicopathological data of 40 patients with glioma were analyzed retrospectively, and the expression of IGF2BP3 in the tumor tissues was analyzed by immunohistochemistry (IHC). Lentiviral vectors harboring short-hairpin RNA (shRNA) were used to knock down IGF2BP3 in the glioma cell lines U87 and U251, and the results were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. The effects of IGF2BP3 on the proliferation, invasion, and tumorigenicity of the glioma cells were verified by Cell Counting Kit-8 (CCK-8), transwell invasion, and subcutaneous tumorigenesis experiments in nude mice. The cell cycle phases were measured by flow cytometry.ResultsThe sequencing of TCGA data identified IGF2BP3 as the most significantly altered m6A-related gene. Patients with high IGF2BP3 expression had a significantly reduced survival probability (P<0.001) compared to those with low IGF2BP3 expression. IGF2BP3 was more upregulated in the HGGs than the LGGs. The downregulation of IGF2BP3 inhibited the proliferation, migration, and invasiveness of the glioma cells, and xenograft tumor growth in the mice. According to TCGA data, IGF2BP3 was closely related to cell cycle regulators, such as cyclin-dependent kinase 1 (CDK1) and cell-division cycle protein 20 homologue (CDC20). Further, the knockdown of IGF2BP3 affected the expression of CDK1 and the cell cycle process.ConclusionsIGF2BP3 expression in glioma is positively correlated with tumor grade and enhanced glioma cell proliferation, invasion, and tumorigenicity. IGF2BP3 knockdown decreased the expression of CDK1 and the cell cycle process. The current study showed that IGF2BP3 may serve as a biomarker of prognosis and a therapeutic target in glioma.

Project description:BackgroundInsulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported to exhibit an oncogenic effect as an RNA-binding protein (RBP) by promoting tumor cell proliferation, migration and invasion in several tumor types. However, a pan-cancer analysis of IGF2BP3 is not currently available, and the exact roles of IGF2BP3 in prognosis and immunology in cancer patients remain enigmatic. The main aim of this study was to provide visualization of the systemic prognostic landscape of IGF2BP3 in pan-cancer and to uncover the potential relationship between IGF2BP3 expression in the tumor microenvironment and immune infiltration profile.MethodsRaw data on IGF2BP3 expression were obtained from GTEx, CCLE, TCGA, and HPA data portals. We have investigated the expression patterns, diagnostic and prognostic significance, mutation landscapes, functional analysis, and functional states of IGF2BP3 utilizing multiple databases, including HPA, TISIDB, cBioPortal, GeneMANIA, GESA, and CancerSEA. Moreover, the relationship of IGF2BP3 expression with immune infiltrates, TMB, MSI and immune-related genes was evaluated in pan-cancer. IGF2BP3 with drug sensitivity analysis was performed from the CellMiner database. Furthermore, the expression of IGF2BP3 in different grades of glioma was detected by immunohistochemical staining and western blot.ResultsWe found that IGF2BP3 was ubiquitously highly expressed in pan-cancer and significantly correlated with diagnosis, prognosis, TMB, MSI, and drug sensitivity in various types of cancer. Besides, IGF2BP3 was involved in many cancer pathways and varied in different immune and molecular subtypes of cancers. Additionally, IGF2BP3 is critically associated with genetic markers of immunomodulators in various cancers. Finally, we validated that IGF2BP3 protein expression was significantly higher in glioma than in normal tissue, especially in GBM.ConclusionsIGF2BP3 may be a potential molecular biomarker for diagnosis and prognosis in pan-cancer, especially for glioma. It could become a novel therapeutic target for various cancers.

Dataset Information

Depletion of the N⁶-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Publications

Depletion of the N<sup>6</sup>-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Depletion of the N6-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Publications

Depletion of the N<sup>6</sup>-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Depletion of the N⁶-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.