The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells

Dixit, Deobrat; Prager, Briana C.; Gimple, Ryan C.; Poh, Hui Xian; Wang, Yang; Wu, Qiulian; Qiu, Zhixin; Kidwell, Reilly L.; Kim, Leo J.Y.; Xie, Qi; Vitting-Seerup, Kristoffer; Bhargava, Shruti; Dong, Zhen; Jiang, Li; Zhu, Zhe; Hamerlik, Petra; Jaffrey, Samie R.; Zhao, Jing; Wang, Xiuxing; Rich, Jeremy

doi:10.1158/2159-8290.cd-20-0331

Cited by 264 publications

(224 citation statements)

References 80 publications

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“…Readers can decode m 6 A methylation information and convert it into effectors of functional signals. Recently, increasing evidence has shown that changes in m 6 A regulators can promote the development of several cancers ( 20 ), including glioblastoma, breast and cervical cancers, liver and gallbladder cancers, and bladder and prostate cancers ( 21 – 23 ). However, despite some progress in revealing their role in multiple cancers, the characteristics of m 6 A modification in HNSCC are still very inadequate.…”

Section: Introductionmentioning

confidence: 99%

Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma

et al. 2021

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N6-methyladenosine (m6A) plays crucial roles in a diverse range of physiological and pathological processes, and it is believed that it tremendously promotes neoplasia and progression. However, knowledge of the molecular characteristics of m6A modification, its prognostic value, and the infiltration of immune cell populations in head and neck squamous cell carcinoma (HNSCC) is still insufficient. Therefore, a pan-cancer genomic analysis was systematically performed here by examining m6A regulators at the molecular level within 33 multiple cancer types, and the correlations between the expression of m6A molecules were researched using datasets from The Cancer Genome Atlas (TCGA). Based on the above analysis, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is upregulated in HNSCC and may serve as an independent prognostic factor of overall survival, thus showing potential as a prognostic biomarker in HNSCC. Genetic alteration analyses elucidated the reasons for the abnormal upregulation of IGF2BP2 in HNSCC. As a result, IGF2BP2 was selected for further univariate and multivariate analyses. The functions of the related genes were annotated through gene set enrichment analysis, and the activation states of multiple biological pathways were shown by gene set variation analysis. We found that LRRC59 and STIP1 may act as IGF2BP2-associated genes to have a regulatory function in the m6A modification. In addition, we found that the status of immune cell infiltration was correlated with the level of IGF2BP2 gene expression. Our results provide supplementation at the molecular level for epigenetic regulation in HNSCC and insight into effective immunotherapy targets and strategies.

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Section: Introductionmentioning

confidence: 99%

Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma

et al. 2021

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“…According to MODOMIC, a comprehensive database resource for systems biology of RNA modi cation, 172 different RNA chemical modi cations have been found to date in all living organisms, including m6A, which is the most abundant and reversible modi cation, as well as m5C and m7G, Am, Gm and others [13]. Recent studies have demonstrated that various types of cancers, including cervical cancer, hepatocellular carcinoma and glioblastoma, are associated with abnormal m6A abundance [14][15][16]. We characterized the speci c m6A methylation changes and related signaling pathways in Wilms' tumor through experimental and bioinformatics analyses.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening of m6A-modified transcript in the Wilms’ tumor

Liu

et al. 2021

Preprint

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Background Wilms’ tumor, also called nephroblastoma, is the most common pediatric renal malignancy. The pathogenesis of Wilms’ tumor has been attributed to several genetic and epigenetic factors. However, the most pervasive internal mRNA modification that affects almost every process of RNA metabolism, RNA N6-Methyladenosine (m6A) methylation, has not been characterized in Wilms’ tumor. Methods Wilms’ tumor (WT) and adjacent non-cancerous (NC) tissue samples were obtained from 23 children with nephroblastoma, and the global m6A levels were measured by mass spectrometry. Analyses by m6A-mRNA epitranscriptomic microarray and mRNA microarray were performed, and m6A-related mRNAs were validated by quantitative real-time PCR for input and m6A-immunoprecipitated RNA samples from WT and NC tissues. Gene ontology analysis and KEGG pathway analysis were performed for differentially expressed genes, and expression of RNA methylation-related factors was measured by quantitative real-time PCR. Results The total m6A methylation levels in total RNA of WT samples and NC samples were (0.21 ± 0.01)% and (0.22 ± 0.01)%, respectively, with no statistically significant difference. Fifty-nine transcripts were differentially m6A-methylated between the WT and NC groups, which showed distinct m6A modification patterns. Gene ontology analysis indicated that m6A-modified genes were enriched in cancer-associated pathways, including the mTOR pathway, and conjoint analysis of the unique methylation and gene expression patterns in WT samples suggested an association with metabolic pathways.The mRNA levels of the m6A-related “reader” genes, YTHDF1, YTHDF2 and IGF2BP3, were statistically higher in WT samples than in NC samples. Conclusion This is the first study to determine the m6A modification profiles in Wilms’ tumor. Our data provide novel information regarding patterns of m6A modification that correlate with carcinogenesis in Wilms’ tumor.

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“…ZC3H13 was downregulated in colorectal cancer and found to suppress proliferation and invasion via inactivating Ras-ERK pathway [38]. The overexpression of YTHDF2 was observed in liver cancer, AML and GBM, which was implicated in the stemness maintenance of cancer stem cells [19,39,40]. HNRNPA2B1 was highly expressed in multiple types of cancer, and it promoted the proliferation of breast cancer cells through STAT3 pathway [41].…”

Section: Discussionmentioning

confidence: 99%

Expression Status and Prognostic Roles of m6A-related Genes in Multiple Myeloma: YTHDF2 as the independent prognostic factor

Li¹,

Shen²,

Wu³

et al. 2021

Preprint

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Background: N6-methyladenosine is the most abundant RNA modification, which plays a prominent role in multiple biology processes, including tumorigenesis. Multiple myeloma (MM) is the second most frequent hematological cancer. However, the expression status and value of m6A-related genes in multiple myeloma remain elusive.Methods: m6A-related gene expression data and clinical information of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Based on differentially expressed analysis, protein-protein interaction (PPI) analysis, Pearson correlation analysis, Kaplan-Meier survival analysis and Cox regression analysis, the prognostic m6A-associated genes were identified. The receiver operation characteristic (ROC) curves were used to verify the prognostic and diagnostic efficiency. The molecular mechanisms were investigated by differentially expressed mRNA and microRNA analyses with the help of online database ENCORI and POSTAR.Results: Among 22 m6A-related genes, HNRNPC, RBM15B, RBM15, YTHDF3, YTHDF2, HNRNPA2B1 and IGF2BP2 were significantly upregulated, while ZC3H13, FTO, IGF2BP3, ALKBH5 and YTHDC1 were significantly downregulated in MM patients. The high expression of HNRNPC, HNRNPA2B1, YTHDF2 and the low expression of ZC3H13 were associated with adverse survival. Furthermore, the expression level of YTHDF2 was the independent prognostic factor of MM. ROC curves suggested the great prediction performance for MM patients. Differentially expressed mRNA and microRNA analyses indicated the probable involvement of miR-205/YTHDF2/EGR1 axis.Conclusions: Our study first systematically analyzed the expression status of m6A-related genes in multiple myeloma, identified HNRNPC, HNRNPA2B1, YTHDF2 and ZC3H13 that could be the potential prognostic biomarkers, especially YTHDF2, which may be implicated in the miR-205/YTHDF2/EGR1 axis.

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The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells

Cited by 264 publications

References 80 publications

Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma

Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma

Genome-wide screening of m6A-modified transcript in the Wilms’ tumor

Expression Status and Prognostic Roles of m6A-related Genes in Multiple Myeloma: YTHDF2 as the independent prognostic factor

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