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EGFR/Src/Erk-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma [RNA-Seq]

ABSTRACT: Epidermal growth factor receptor (EGFR) signaling is constitutively activated in majority of GBM and is associated with a worse prognosis. Here we show that EGFR is responsible for overexpression of the m6A "reader" YTHDF2 in GBM through the EGFR/Src/ERK signaling pathway. YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR signaling stabilizes YTHDF2 protein through phosphorylation of YTHDF2 serine 39 and threonine 381 by ERK1/2. YTHDF2 is required for GBM cell proliferation, invasion and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, both are genes impacting glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells largely through downregulation of LXRA and HIVEP2. Further, YTHDF2 inhibits LXRA-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover novel function for YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142825 | GEO | 2020/10/08

REPOSITORIES: GEO

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EGFR/Src/Erk-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma [RIP-Seq]

Project description:Epidermal growth factor receptor (EGFR) signaling is constitutively activated in majority of GBM and is associated with a worse prognosis. Here we show that EGFR is responsible for overexpression of the m6A "reader" YTHDF2 in GBM through the EGFR/Src/ERK signaling pathway. YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR signaling stabilizes YTHDF2 protein through phosphorylation of YTHDF2 serine 39 and threonine 381 by ERK1/2. YTHDF2 is required for GBM cell proliferation, invasion and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, both are genes impacting glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells largely through downregulation of LXRA and HIVEP2. Further, YTHDF2 inhibits LXRA-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover novel function for YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.

2020-10-08 | GSE142827 | GEO

Genotyping by array of 123 IDH WT glioblastomas

Project description:Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy.GBM is one of the most genetically unstable cancers. It is characterized by numerous chromosome (chr) copy number alterations (CNA), such as chr 7 gain, chr 9p loss, and chr 10 loss, along with CDKN2A homozygous deletion (chr 9p21) and EGFR amplification (chr 7p11).Chromosome instability (CIN) may be the cause or the consequence of GBM development. In high-grade diffuse gliomas (HGG), CIN may initiate tumorigenesis. To identify recurrent genomic abnormalities in IDH WT glioblastomas, SNP arrays (Illumina 850K CytoSNP) were analyzed for 123 IDH WT GBM cases.

2018-02-27 | E-MTAB-6371 | biostudies-arrayexpress

m6A-dependent regulation of messenger RNA stability

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification present in the mRNA of all higher eukaryotes. Here we present that m6A is selectively recognized by human YTH domain family (YTHDF2) protein to regulate mRNA degradation. By using crosslinking and immunoprecipitation, we have identified over 4000 substrate RNA of YTHDF2 with conserved core motif of G(m6A)C. We further estabilshed the role of YTHDF2 in RNA metabolism by a combination of ribosome profiling, RNA sequencing, m6A level quantification and cell-based imaging: the C-terminal domain of YTHDF2 selectively binds to m6A of mRNA and the N-terminal domain is responsive for localizing mRNA from translatable pool to processing body where mRNA decay occurs. PAR-CLIP and RIP was used to identify YTHDF2 binding sites followed by ribosome profling and RNA seq to assess the consequences of YTHDF2 siRNA knock-down

2013-11-29 | E-GEOD-49339 | biostudies-arrayexpress

RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/ β-catenin signaling

Project description:Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/β-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/β-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression.

2021-05-19 | GSE161090 | GEO

m6A meRIP-Seq from Ythdf2CTL pre-leukemic cells

Project description:The mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human acute myeloid leukemias (AML). To understand the role of YTHDF2 in AML, we generated m6A meRIP-seq libraries form Ythdf2fl/fl (Ythdf2CTL) pre-leukemic cells.

2019-04-05 | E-MTAB-6791 | biostudies-arrayexpress

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2019-04-05 | E-MTAB-7783 | biostudies-arrayexpress

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

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

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EGFR Mutation Promotes Glioblastoma Through Epigenome and Transcription Factor Network Remodeling

Project description:Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in Glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy. ChIP-Seq for H3K27ac, H3K4me1, and H3K4me3, and RNA-seq for Glioblastoma (GBM) cells and/or tissues with or without EGFRvIII mutation.

2015-09-14 | E-GEOD-72468 | biostudies-arrayexpress

CHRM3 is a novel prognostic factor of poor prognosis and promotes GBM progression via activation of oncogenic invasive growth factors

Project description:Glioblastoma (GBM) is the most aggressive cancer in brain and contains a high mortality ratedue to lack of effective treatment strategy. Molecular mechanisms of GBM characteristic invasive growth are urgently need to improve the poor prognosis. Via single nuclear-sequences of primary and recurrent GBM samples, level of the M3 muscarinic acetylcholine receptor (CHRM3) was significantly higher in recurrent samples. Moreover, immunohistochemical staining of an array of glioma samples showed that high levels of CHRM3 is correlated to poor prognosis of glioma, consistent with The Cancer Genome Atlas (TCGA) database. Knockdown of CHRM3 retarded glioma cell growth and invasion. In vivo assay of orthotopic glioma animal model indicated that inhibition of CHRM3 significantly suppressed glioma progression with prolonged survival time. Transcriptome analysis revealed that CHRM3 knockdown significantly reduced array of classic factors involved in cancer invasive growth including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8. Taken together, our study identified that CHRM3 is a new and important factor of GBM progression via regulation of multiple oncogenic genes and these results provide a new biomarker for prognosis and therapy of GBM patients.

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