METTL3 mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743037 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15014802.fastq.gz | Fastqsanger.gz | |||
| SRR15014803.fastq.gz | Fastqsanger.gz | |||
| SRR15014804.fastq.gz | Fastqsanger.gz | |||
| SRR15115758.fastq.gz | Fastqsanger.gz | |||
| SRR15115759.fastq.gz | Fastqsanger.gz |
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Project description:Esophageal cancer is a lethal malignancy with high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are stillis poorly understood. Here we found that the N6-methyladenosine (m6A) methyltransferase METTL3 is significantly up-regulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that Mettl3 mediated m6A modification is essential for promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of Mettl3 in promoting in vivo ESCC tumorigenesis in vitro and in vivo. Mechanistically, Mettl3 catalyzed m6A modification promotes NOTCH1 expression and the activation of Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration and invasion capacities of METTL3 depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.
2021-09-15 | GSE179267 | GEO
Project description:Liver-specific deficiency of Mettl3 causes liver injury. By performing RNA sequencing (RNA-seq) analysis on the Mettl3-deficient versus control livers, we identified the potential target genes that were closely associated with the liver phenotype in liver-specific Mettl3 knockout mice. RNA-seq analysis revealed extensive metabolic reprogramming in Mettl3-deficient livers. These results demonstrated that Mettl3 coordinates metabolic homeostasis and functional maturation during postnatal liver development.
2022-03-09 | GSE197799 | GEO
Project description:N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of new born cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
2018-07-15 | GSE100528 | GEO
Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells
2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress
Project description:Epigenetic changes present in many physiological and pathological processes. The N6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) is still elusive. Here, the level of m6A modification was significantly upregulated in podocytes stimulated by high glucose (HG), which was caused by elevated levels of METTL3. The results were consistent in the streptozotocin (STZ)-induced experimental model of type 1 diabetes and db/db type 2 diabetes mice. Knocking out METTL3 significantly reduced the inflammation and apoptosis of HG-stimulated podocytes, while its overexpression significantly aggravated these responses. More importantly, silencing METTL3 both in type 1 and type 2 diabetic mice in vivo significantly reduced urinary albumin excretion and histopathological injury. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of its target gene, TIMP2, and exerted pro-inflammatory and pro-apoptotic effects. Moreover, METTL3 enhanced the stability of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.
2024-12-08 | GSE190436 | GEO
Project description:Esophageal cancer is a lethal malignancy with a high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are still poorly understood. Here, we found that the N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that 3METTL3-mediated m6A modification promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis in vitro and in vivo. Mechanistically, METTL3-catalyzed m6A modification promotes NOTCH1 expression and the activation of the Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration, and invasion capacities of METTL3-depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.
| S-EPMC8416973 | biostudies-literature
Project description:METTL3 and METTL14 are considered to faithfully form the m6A writing complex in a 1:1 ratio, regulating the fate of mRNA by adding m6A modifications. However, recent studies have shown inconsistent expression and prognostic value of METTL3 and METTL14 in some tumors, suggesting that they may not be faithful in tumors. Pan-cancer analysis based on TCGA data reveals significant differences in expression, function, tumor burden correlation, and immune correlation between METTL3 and METTL14, especially in esophageal squamous cell carcinoma (ESCC). Knockdown of METTL3 significantly inhibits the cell proliferation in vitro and in vivo in ESCC EC109 cells, while the impact of METTL14 knockdown on proliferation is limited, and it cannot abolish the expression of METTL3 protein. mRNA-seq results indicate that METTL3 independently regulates the expression of 1615 genes, while only 776 genes are co-regulated by METTL3 and METTL14. Furthermore, through immunofluorescence co-localization, it is observed that METTL3 and METTL14 have certain inconsistencies in cellular localization. HPLC-MS results show that METTL3 independently binds to the Nop56p-associated pre-rRNA complex and mRNA splicing complex, separate from METTL14. Through bioinformatics and various omics studies, we have preliminarily discovered that METTL3 independently regulating tumor cell proliferation, and the participation in mRNA splicing may be a critical molecular mechanism. Our study provides an experimental basis and theoretical foundation for further understanding of the m6A writing complex and tumor therapy targeting METTL3.
2024-02-01 | PXD048886 | Pride
Project description:Bladder cancer characterized by RNA methylation abnormalities and NOTCH pathway dysregulation exhibits high recurrence that remains the major obstacle for bladder cancer treatment. Targeting methyltransferase-like 3 (METTL3) and NOTCH signal is a potential strategy to block bladder cancer progression. However, the underlying mechanisms by which METTL3-manipulated NOTCH signal and its effect on bladder cancer tumorigenesis remain to be clarified. Here we showed that METTL3-guided m6A modification methylated pri-miR-146 at the flaking sequence, which was responsible for the pri-miR-146 maturation. Furthermore, NUMB/NOTCH2 axis was identified as the functional downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Therapeutically, the polypeptide melittin was demonstrated to induce apoptosis of bladder cancer cells in a METTL3-dependent manner. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of bladder cancer patient. Our studies indicate that METTL3/miR-146a-5p/NUMB/NOTCH2 axis could be a potential therapeutic target for recurrent bladder cancer treatment and METTL3 acts as a fate determinant that controls sensitivity of bladder cancer cells to melittin treatment.
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Project description:To investigate the role of METTL3-mediated m6A modification, we performed m6A-sequencing to map the m6A modification in control or METTL3 knockdown BGC823 cells.
2019-10-29 | GSE133132 | GEO
Project description:We have perturbed RNA methylation machinery and investigated the change in subcellular localization of mRNA in Ascl1-induced neurons (iNeurons). Mutant iNeuron line harbouring tagged endogenous Mettl3 was generated which allowed for the selective and targeted depletion of Mettl3 protein with the addition of dTAG. Cells were treated with dTAG for 40 hours then separated into compartments (neurites and soma) and then sequenced in parallel with samples which received no dTAG treatment.
2023-07-12 | E-MTAB-9643 | biostudies-arrayexpress