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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 [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 [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.

Project description:Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. In addition, the knowledge of the disease-associated expression and function of YTHDF2 remains very limited. Here, we show that YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR that is constitutively activated in the majority of GBM causes YTHDF2 overexpression through the EGFR/SRC/ERK pathway. EGFR/SRC/ERK signaling phosphorylates YTHDF2 serine39 and threonine381, thereby stabilizes YTHDF2 protein. YTHDF2 is required for GBM cell proliferation, invasion, and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, which impacts the glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells, largely through the downregulation of LXRα and HIVEP2. Furthermore, YTHDF2 inhibits LXRα-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover the function of YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.

| 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

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

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

Project description:BackgroundThe use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.MethodsEGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.ResultsLong-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.ConclusionsOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.

| S-EPMC8932110 | biostudies-literature

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

Project description: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.

2021-07-02 | GSE137258 | GEO

Microarray profiling of YTHDF2 deficient mouse oocytes

Project description:To study the role of the protein YTHDF2 during female gametogenesis, its gene was conditionally deleted in oocytes. Total RNA samples from YTHDF2 deficient GV and MII oocytes (and control oocytes) were subjected to array profiling.

2018-02-12 | E-MTAB-5576 | biostudies-arrayexpress

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