Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer

ABSTRACT: We found in this study through targeted CRISPR-Cas9 screening of RBPs that disrupting YTHDF2-dependent degradation of its target transcripts triggers apoptosis of MYC-dependent cancer cells and tumors. Enhanced CLIP (eCLIP), m6A-sequencing (m6A-seq) and YTHDF2 knockdown followed by RNA-seq analysis of YTHDF2-m6A-mRNA interactions revealed extensive associations with mRNAs encoding MAPK pathway genes that when stabilized, induce epithelial-to-mesenchymal transition and stress-induced apoptosis. scRibo-STAMP profiling of translating mRNAs revealed global alterations in the translatome of single cells in YTHDF2-depleted solid tumors. Thus, our work highlights the therapeutic relevance of RBPs by uncovering the critical role of YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven cancers.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE137258 | GEO | 2021/07/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

YTHDF2 iCLIP in glioblastoma stem cells

Project description:Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSCs). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA-immunoprecipitation followed by sequencing (meRIP-seq) and transcriptome analysis, finding transcripts marked by m6A often upregulated. Interrogating m6A regulators, GSCs displayed preferential expression as well as in vitro and in vivo dependency of the m6A reader, YTHDF2, in contrast to normal neural stem cells (NSCs). While YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized the oncogene transcripts, MYC and VEGFA, in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs and IGF1/IGF1R inhibitor, Linsitinib, as preferentially targeting YTHDF2-expressing cells, inhibiting the viability of GSCs without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma.

2020-09-29 | GSE158020 | GEO

The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [RNA-seq]

2020-09-29 | GSE158740 | GEO

The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [m6A RIP-seq]

2020-09-29 | GSE158741 | GEO

YTHDF2 mediates the mRNA degradation in prostate cancer in m6A-dependent way

Project description:As the crucial m6A reader, YTHDF2 usually degrades the target mRNAs by recognizing the m6A modified sites, consequently altering m6A levels of each mRNA. In this study, we used m6A MeRIP sequencing to detect the m6A modification alterations in prostate cancer (PCa) cell line after knocking down YTHDF2 and identify how YTHDF2 promote the PCa progression by mediating the mRNA degradation in m6A-dependent way.

2020-11-09 | GSE129408 | GEO

Expression data from YTHDF1 or YTHDF2 down-regulated PC9

Project description:The human YTH domain family protein (YTHDF) family is RNA binding protein which specifically recognizes N6-methyladenosine (m6A), and exerts distinct roles in eukaryocytes; YTHDF1 promotes the translation of m6A modified mRNAs collaborating with initiation factors, and YTHDF2 reduces the stability of the m6A-modified transcripts. We used the Nanostring nCounter to detail the differential gene expression by YTHDF1 and YTHDF2.

2021-08-24 | GSE171634 | GEO

Ythdf2-mediated m6A mRNA clearance modulates neural development in mice

Project description:We found that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 null mutants.To explore the underlying molecular mechanism, we performed transcriptomics and well-established m6A-methylome analyses of NSPCs dervied from wild type and Ythdf2-/- embryo brains. RNA-seq data revealed that expressions of genes enriched in neural development pathways were significantly disturbed. The inhibitory genes, like Flrt2, Ptprd, et al. in regulation of JAK-STAT cascade, which contributes to the neuroprotection and neurite outgrowth, showed increased gene expressions and m6A enrichment by m6A-seq. We identified that without the recognizing and binding of Ythdf2, the degradation of neuron differentiation related m6A-modified mRNAs were delayed in Ythdf2-/-, thereby disturbing the proliferation and differentiation of NSPCs. In summary, our findings uncovered that Ythdf2 modulates neural developmental via regulating the clearance of mRNA targets.

2018-01-01 | GSE104867 | GEO

Hypoxia perturbs m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma

Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to eventually stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.

2020-03-17 | GSE120860 | GEO

Anti-YTHDF2 RIP-Seq to identify YTHDF2 target mRNAs in hippocampus

Project description:To identify the target mRNAs of the m6A reader protein YTHDF2 in mouse hippocampus, we carired out anti YTHDF2 RNA Immunoprecipitation (RIP) followed by RNA-sequencencing. Using EZ-Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit (Millipore), RNA from P40 wild type mouse hippocampus was pulled down by rabbit polyclonal anti-YTHDF2 (proteintech) and then sequenced on Illumina Novaseq 6000. The filtered reads were aligned to the mouse reference genome (GRCm38) using BWA mem (v 0.7.12).Then the MACS2 (version 2.1.0) peak calling software was used to identify regions of IP enrichment over background, followed by the motif detected by Homer (Heinz et al., 2010). Peak related genes are then confirmed by PeakAnnotator. Different peak analysis was based on the fold enrichment of peaks of different experiments. A peak was determined as different peak when the odds ratio between two groups was more than 2. Using the same method, genes associated with different peaks were identified. Finally, Biological replicates of anti-YTHDF2 RIP-Seq identified 408 mRNAs transcripts. This study provides gene lists which shows mRNA binding with YTHDF2 in mouse hippocampus.

2023-01-19 | GSE171791 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of normal and YTHDF2 Overexpressing SMMC7721 cells in normoxia and hypoxia condition

Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia restrains the ‘reader’ protein YTH domain family 2 (YTHDF2), to stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.

2020-03-17 | GSE120611 | GEO

Identification of m6A-modified YTHDF2 targets by high-throughput m6A-seq and RIP-seq in HBV-infected HepG2 cells [m6A-seq]

Project description:We investigated the role of O-GlcNAcylation of m6A reader YTHDF2 in HBV-related hepatocarcinogenesis and progression. We found that YTHDF2 O-GlcNAcylation was elevated upon HBV infection through upregulated HBP. OGT-mediated YTHDF2 O-GlcNAcylation at Ser263 enhanced its protein stability, and subsequently changed the gene expression profiles. Mechanistically, we identified YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 mRNAs in an m6A dependent manner by high-throughput profiling of m6A-seq and RIP-seq, thereby promoting HBV-related HCC tumorigenesis. Importantly, our study proposed that targeting OGT-mediated YTHDF2 O-GlcNAcylation may be a novel strategy for potential treatment of HBV-associated liver cancer.

2023-02-15 | GSE200260 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data