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EGFR/Src/Erk-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma

ABSTRACT: EGFR/Src/Erk-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma

PROVIDER: PRJNA598562 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10814896.fastq.gz	Fastqsanger.gz
	SRR10814897.fastq.gz	Fastqsanger.gz
	SRR10814898.fastq.gz	Fastqsanger.gz
	SRR10814899.fastq.gz	Fastqsanger.gz
	SRR12539168.fastq.gz	Fastqsanger.gz

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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

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

2020-10-08 | GSE142825 | GEO

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

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

| PRJNA598564 | ENA

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

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

| PRJNA598565 | ENA

EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma.

Project description: Not available

| S-EPMC7794382 | biostudies-literature

EGFR/Src/Erk-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-08 | GSE142828 | GEO

O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma

Project description:The intracellular O-linked N-acetylglucosamine (O-GlcNAc) glycosylation mediates many signal transduction events and regulates tumorigenesis. Previously the RNA N6-methyladenosine (m6A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), has been shown to be O-GlcNAcylated on Ser-263 during Hepatitis B virus (HBV) infection and promote HBV-related hepatocellular carcinoma. Herein we mapped YTHDF2 O-GlcNAcylation at Thr-49 via electron-transfer dissociation mass spectrometry under unperturbed conditions. We show that YTHDF2 Thr-49 O-GlcNAcylation antagonizes Extracellular-signal regulated kinase (ERK)-dependent phosphorylation at Ser-39 and promotes YTHDF2 degradation. The downstream signaling pathway of YTHDF2 in lung carcinoma are thus upregulated, which leads to the downregulation of c-Myc. We further used mouse xenograft models to show that YTHDF2-T49A mutants increased lung cancer mass and size. Our work reveals a key role of YTHDF2 O-GlcNAcylation in tumorigenesis and suggests that O-GlcNAcylation exerts distinct functions under different biological stress.

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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.

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Activation of the SRC/MEK/ERK Pathway by Arsenic Disulfide Restores Megakaryopoiesis and Platelet Production in Myelodysplastic Syndrome

Project description:Thrombocytopenia is a common and clinically significant complication of myelodysplastic syndrome (MDS), but effective therapies directly targeting megakaryopoiesis are limited. Sanzi Huangshi Pill (SZHSP), a traditional Chinese medicine formula containing arsenic disulfide (As2S2), has been found to have haematopoietic effects in clinical settings, but the mechanisms involved have yet to be fully explained. In this study, the effects of SZHSP and As2S2 on megakaryocyte differentiation were evaluated in NUP98-HOXD13 transgenic mice and Meg-01 cells. Through haematological analyses, flow cytometry, molecular assays, network pharmacology, RNA sequencing, and pharmacological inhibition studies, we found that SZHSP significantly improved thrombocytopenia in MDS mice, increased the proportion of mature CD41+CD42+ megakaryocytes, and up-regulated the expression of Gata-1, Fog1, and Fli1. In vitro, both SZHSP-containing serum and As2S2 induced megakaryocytic differentiation and increased lineage-associated markers in Meg-01 cells. Transcriptomic analysis and network pharmacology demonstrated the activation of MAPK-related pathways and megakaryopoiesis-associated gene programs, identifying SRC and MAPK signaling as important regulatory nodes. Mechanistic studies further revealed that As2S2 increased the phosphorylation of SRC, MEK, and ERK, and the pharmacological inhibition of SRC significantly reduced the differentiation-promoting effects of As2S2. In conclusion, SZHSP and its major active ingredient As2S2 promote megakaryocyte differentiation and platelet recovery by activating the SRC/MEK/ERK signaling pathway, offering mechanistic evidence for SZHSP as a potential differentiation-based therapeutic approach for MDS-associated thrombocytopenia.

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Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression.

Project description: Not available

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