The biological function of m6A demethylase ALKBH5 and its role in human disease

Wang, Jinyan; Wang, Jinqiu; Gu, Quan; Ma, Yajun; Yang, Yan; Zhu, Jing; Zhang, Quan’an

doi:10.1186/s12935-020-01450-1

Cited by 133 publications

(116 citation statements)

References 49 publications

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“…ALKBH5 contains a DSBH domain, which can bind to the ATP domain of DDX3 gene, thus affecting cell cycle, apoptosis, RNA degradation and other cellular processes [31]. In the present study, ALKBH5 expressions was varied in different malignant tumors.…”

Section: Discussionmentioning

confidence: 58%

Expression and Prognostic Significance of m6A-Related Genes in TP53-Mutant Non-small-cell Lung Cancer

Zhao

Wan

Guo

et al. 2020

Preprint

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BackgroundTP53 is an important tumor suppressor gene located on human chromosome 17. TP53 mutations have been confirmed in more than 60% of tumor patients' somatic cells. N6-methyladenosine is an enzyme that plays an important role in mRNA splicing, translation, and stabilization. It is a common internal modification of nucleotides, that is regulated by methyltransferases ("writer"), binding proteins ("reader"), and demethylases ("eraser"). However, its role in TP53 mutant non-small-cell lung cancer remains unknown. In this study, we investigated 17 common N-6-Methyladenosine regulators' contributions and prognostic values.Methods and MaterialsThe expression sets of 233 TP53 mutant NSCLC and 236 TP53 wild type NSCLC patients were downloaded from the Cancer Genome Atlas (TCGA) databases with their simple nucleotide variation and their clinical messages. 17 m6A regulators were systematically analyzed in our study, which including 8 "writers" (METTL3/14/16, WTAP, RBM15/15B, KIAA1429, ZC3H13), 7 "readers" (YTHDF1/2/3, YTHDC1/2, HNRNPA2B1, HNRNPC), 2 "erasers" (FTO, ALKBH5). Consensus clustering was used to classify TP53 mutant NSCLC and TP53 wild type NSCLC into two subgroups. Univariate and multivariate cox regression were used to construct a prognostic signature and compute risk score based to m6A regulators’ expression in TP53 mutant and wild type NSCLC. Gene Ontology (GO), Gene Set enrich analysis (GSEA), STRING and Cytoscape tools were used to find different signaling pathways and biological processes between TP53 mutant and wild type NSCLC.ResultsWilcox test showed that 9 of 17 m6A regulators were expressed differently between TP53 mutant and wild type NSCLC (p < 0.05). Then consensus clustering has been used for tumor typing and a new way of typing is attempted, while the groups obtained by consensus clustering couldn’t predict prognostic well in mutant and wild type patients (p = 0.121 in wild type and p = 0.089 in mutant). Using univariate cox regression analysis, ALKBH5, HNRNPA2B1 were associated with the prognostic of TP53 mutant patients. Then we built signatures of N-6-Methyladenosine regulators with prognostic ability based on the multivariate cox regression in TP53 mutant cohorts. Moreover, we found that this signature could predict the prognostic in mutant cohort well (p < 0.001, AUG > 0.6). With this signature, patients with TP53 mutations can be divided into high and low risk groups. Finally, we found 338 DEGs between high and low risk groups, then GO enrichment analysis, PPI network was used to analysis different signaling pathways between two groups.ConclusionIn conclusion, our study showed m6A regulators can be used as predictive prognostic tools in TP53 mutant patients.

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Section: Discussionmentioning

confidence: 58%

Expression and Prognostic Significance of m6A-Related Genes in TP53-Mutant Non-small-cell Lung Cancer

Zhao

Wan

Guo

et al. 2020

Preprint

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“…YTHDF2, as a member of m6A "readers", can selectively recognize and bind to m6A-containing RNA to initiate its degradation in a deadenylation-dependent manner by interacting directly with the SH domain of CNOT1, the scaffolding subunit of the CCR4-NOT deadenylase complex [33]. Accumulating evidences have demonstrated that YTHDF2 can act as an oncogene cooperating with dysregulated "writers" or "erasers" via degrading m6A-containg tumor-inhibiting factors [49]. For example, the overexpression of METTL3 and YTHDF2 in bladder cancer can promote cell proliferation and migration via the decay of tumor suppressors Kruppel-like factor 4 (KLF4) and SET domain containing 7 (SETD7) [50].…”

Section: Discussionmentioning

confidence: 99%

“…The installation of m6A is catalyzed by writers/methyltransferase complex (MTX), including methyltransferase-like protein 3 (METTL3), METTL14, METTL16, WT1-associated protein (WTAP), RNA-binding motif protein 15 (RBM15), RBM15B, KIAA1429 (or named VIRMA) and zinc nger CCCH-type containing 13 (ZC3H13) [9,10]. Eraser is a class of demethylases, including fat mass and obesity-associated protein (FTO), α-ketoglutarate-dependent dioxygenase homolog 5 (ALKBH5) and ALKBH3 [11][12][13]. Read proteins can recognize speci c m6A sites and regulate the biofunction of target RNA.…”

Section: Introductionmentioning

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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“…NANOG contributes to tumor cell growth and TMZ resistance in glioma [19,20]. N6-methyladenosine (m6A) is a common mRNA modi cation, and it is involved in the regulation of noncoding RNAs on tumorigenesis [21].AlkB homolog H5 (ALKBH5) is a representative m6A demethylase which can lead to the demethylation of mRNA in human disease [22]. ALKBH5 maintains tumorigenicity of glioma stem-like cells [23].…”

Section: Introductionmentioning

confidence: 99%

Warburg Effect-Promoted Exosomal Circ_0072083 Releasing Up-Regulates Nango Expression Through Multiple Pathways and Enhances Temozolomide Resistance in Glioma

Ding

Chen

et al. 2020

Preprint

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BackgroundTemozolomide (TMZ) resistance limits its application in glioma. Exosome can carry circular RNAs (circRNAs) to regulate drug resistance via sponging microRNAs (miRNAs). miRNAs can control mRNA expression by regulate the interaction with 3’UTR and methylation. Nanog homeobox (NANOG) is an important biomarker for TMZ resistance. Hitherto, it is unknown about the role of exosomal hsa_circ_0072083 (circ_0072083) in TMZ resistance in glioma, and whether it is associated with NANOG via regulating miRNA sponge and methylation.MethodsTMZ-resistant (n=36) and sensitive (n=33) patients were recruited. The sensitive cells and constructed resistant cells were cultured and exposed to TMZ. circ_0072083, miR-1252-5p, AlkB homolog H5 (ALKBH5) and NANOG levels were examined via quantitative reverse transcription polymerase chain reaction and western blot. The half maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, migration and invasion were analyzed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing and transwell assays. The in vivo function was assessed using xenograft model. The N6-methyladenosine (m6A) level was analyzed via methylated RNA immunoprecipitation (MeRIP). Target relationship was investigated via dual-luciferase reporter assay and RNA immunoprecipitation. Warburg effect was investigated via lactate production, glucose uptake and key enzymes expression. Exosome was isolated and confirmed via transmission electron microscopy and specific protein expression.Resultscirc_0072083 expression was increased in TMZ-resistant glioma tissues and cells. circ_0072083 knockdown restrained the resistance of resistant cells via decreasing IC50 of TMZ, proliferation, migration, invasion and xenograft tumor growth and increasing apoptosis. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation. circ_0072083 could regulate NANOG and ALKBH5 via targeting miR-1252-5p to control TMZ resistance. Warburg effect promoted the release of exosomal circ_0072083 in resistant cells. Exosomal circ_0072083 from resistant cells increased the resistance of sensitive cells to TMZ in vitro and xenograft model. Exosomal circ_0072083 level was enhanced in resistant patients, and it had a diagnostic value and indicated a lower overall survival in glioma. ConclusionExosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

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The biological function of m6A demethylase ALKBH5 and its role in human disease

Cited by 133 publications

References 49 publications

Expression and Prognostic Significance of m6A-Related Genes in TP53-Mutant Non-small-cell Lung Cancer

Expression and Prognostic Significance of m6A-Related Genes in TP53-Mutant Non-small-cell Lung Cancer

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

Warburg Effect-Promoted Exosomal Circ_0072083 Releasing Up-Regulates Nango Expression Through Multiple Pathways and Enhances Temozolomide Resistance in Glioma

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