RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA599373 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10842882_1.fastq.gz | Fastqsanger.gz | |||
| SRR10842882_2.fastq.gz | Fastqsanger.gz | |||
| SRR10842883_1.fastq.gz | Fastqsanger.gz | |||
| SRR10842883_2.fastq.gz | Fastqsanger.gz | |||
| SRR10842884_1.fastq.gz | Fastqsanger.gz |
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Project description:N6-methyladenosine (m6A) is a type of nucleotide modification abundant in mRNA, which regulates mRNA stability, splicing and translation. However, its physiological role in intratumoral microenvironment and drug resistancehave not been fully understood. We demonstrated that METTL3,a primary m6A methyltransferase, was significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promoted sorafenib-resistance and angiogenesis and exacerbated progression by activating autophagy-associated pathway. Mechanistically, we identified FOXO3 as a key downstream target of the METTL3-mediated m6A modification. The m6A modification of FOXO3 at the 3'-untranslated region increased FOXO3 mRNA stability. Analysis of clinical samples showed that METTL3levels aretightly correlated with FOXO3levels in patients with HCC, and suppression of FOXO3 predicted poor clinical outcomes. Importantly, METTL3-depletion significantly enhanced sorafenib-resistance of HCC via a METTL3-FOXO3 axis, whereasoverexpression of FOXO3 restored the m6A-dependent sorafenib-sensitivity. Collectively, our work revealedthe critical function of the METTL3-mediated m6A modification in HCC in hypoxic tumor microenvironment, and provided insights into the molecular mechanism of the m6A modification in the resistance of HCC to sorafenib therapy.
2020-04-03 | GSE143234 | GEO
Project description:N6-methyladenosine (m6A) is a type of nucleotide modification abundant in mRNA, which regulates mRNA stability, splicing and translation. However, its physiological role in intratumoral microenvironment and drug resistancehave not been fully understood. We demonstrated that METTL3,a primary m6A methyltransferase, was significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promoted sorafenib-resistance and angiogenesis and exacerbated progression by activating autophagy-associated pathway. Mechanistically, we identified FOXO3 as a key downstream target of the METTL3-mediated m6A modification. The m6A modification of FOXO3 at the 3'-untranslated region increased FOXO3 mRNA stability. Analysis of clinical samples showed that METTL3levels aretightly correlated with FOXO3levels in patients with HCC, and suppression of FOXO3 predicted poor clinical outcomes. Importantly, METTL3-depletion significantly enhanced sorafenib-resistance of HCC via a METTL3-FOXO3 axis, whereasoverexpression of FOXO3 restored the m6A-dependent sorafenib-sensitivity. Collectively, our work revealedthe critical function of the METTL3-mediated m6A modification in HCC in hypoxic tumor microenvironment, and provided insights into the molecular mechanism of the m6A modification in the resistance of HCC to sorafenib therapy.
2020-04-03 | GSE143233 | GEO
Project description:RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy
| PRJNA599368 | ENA
Project description:RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy [m6A RIP-seq]
| PRJNA599374 | ENA
Project description:N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells, and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m6A modification in the hypoxic tumor microenvironment, and identifies FOXO3 as an important target of m6A modification in the resistance of HCC to sorafenib therapy.
| S-SCDT-EMBOJ-2019-103181 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-04-03 | GSE143235 | GEO
Project description:Bisphenol A (BPA), a prevalent endocrine disruptor, has been implicated in male reproductive dysfunction, particularly affecting Leydig cells (LCs), which are critical for testosterone production. Here, we explore the impact of BPA on m6A RNA methylation and its regulatory effects on autophagy and LC function. Utilizing both in vivo and in vitro models, we demonstrate that BPA exposure significantly reduces testosterone biosynthesis and upregulates m6A modification in LCs. The m6A 'writer' METTL3 and 'eraser' ALKBH5 were found to play a central role in regulating the m6A levels in Leydig cells upon BPA exposure, and manipulating m6A methylation level mitigates BPA-induced Leydig cell injury.
2025-01-22 | GSE275504 | GEO
Project description:Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that can cause neurotoxicity because of its structural similarity with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an environmental toxin that causes Parkinson’s disease (PD). However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal can significantly enhance the global level of N6-methyladenosine (m6A) mRNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylase FTO (fat mass and obesity-associated protein) and ALKBH5 (alkB homolog 5). The results of the RNA-Seq analysis showed that Sal can exert a neurotoxic effect by regulating the Hippo signaling pathway through RNA methylation. We found that m6A reader YTHDF2 (YTH domain-containing family protein 2) promoted the degradation of m6A-containing YAP1 (Yes-associated protein 1) mRNA, which is a downstream key effector in the Hippo pathway. Additionally, the downregulation of YAP1 can also promote autophagy, indicating that the inter-regulation of YAP1 and autophagy can lead to neurotoxicity. Our findings showed the effect of Sal on m6A RNA methylation and revealed that Sal can act as an RNA modification inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provided greater insights into the neurotoxic effects of catechol isoquinolines and might be used as a reference for further assessing the involvement of RNA methylation in the pathogenesis of PD.
2023-12-04 | GSE249025 | GEO
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism. conditional activation of foxo3 and foxo4 were followed in a timeseries. Each timepoint consists of 4 independent replicates, labeled with either cy3 or cy5 and put on array against time0 as reference.
2012-07-21 | E-GEOD-35703 | biostudies-arrayexpress
Project description:Background - Cardiac microRNAs (miRNAs) could be released into circulation thus becoming circulating cardiac miRNAs, which are increasingly recognized as noninvasive and readily accessible biomarker for multiple heart diseases. A global loss of cardiac miRNAs due to dicer or dgcr8 depletion has been reported to lead to dilated cardiomyopathy (DCM). However, DCM-associated circulating miRNAs (DACMs) and their roles in regulating DCM progression remain largely unexplored. Methods and Results - Through miRNA sequencing of human plasma procured from DCM patients and healthy control people, DCM was characterized with a unique expression pattern for circulating miRNAs. Among them, miR-26a-5p, miR-30c-5p, miR-126-5p, and miR-126-3p were all identified with dramatic reductions in DCM mouse myocardium as in the plasma of DCM patients. FOXO3, highlighted as a predicted common target gene, was experimentally demonstrated to be repressed within cardiomyocytes by these miRNAs except miR-26a-5p. Mechanistically, miRNA combination (miR-30c-5p, miR-126-5p, and miR-126-3p) significantly attenuated FOXO3-induced apoptosis and autophagy observed in cardiomyocytes as well as in DCM murine heart. Cardiac-specific knockout of FOXO3 conspicuously mitigated myocardial apoptosis and autophagy in DCM development. Moreover, stymieing the interaction between these miRNAs and FOXO3 mRNA extremely crippled the cardioprotection of these miRNAs against DCM progression. Cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and autophagy, thereby maintaining cardiac homeostasis and potently preventing DCM development. These findings may provide serological clues for the noninvasive diagnosis of DCM in the future, and unambiguously shed new light on DCM pathogenesis and associated therapeutic targets
2022-07-31 | GSE209991 | GEO