Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

ABSTRACT: Zinc-finger homeobox 3 (ZFHX3, also known as ATBF1) suppresses prostatic tumorigenesis. ZFHX3 is frequently found to have numerous deletions in human prostate cancer (PCa). However, the underlying molecular function of ZFHX3 during prostatic tumorigenesis is not well understood. N6-methyladenosine (m6A) modification in RNA plays a critical role in the development of cancers; however, the relationship between ZFHX3 and m6A modification is largely unknown in PCa. In this study, we found that ZFHX3 knockdown decreased total m6A levels through enhancing the transcriptional activity of FTO in PCa cells. Importantly, FTO inhibition suppressed cell proliferation and rescued the promoting function of ZFHX3 knockdown on cell proliferation. In vivo, we verified that FTO was upregulated and ZFHX3 was decreased in PCa patients and that a high level of ZFHX3 is indispensable for low FTO expression and is correlated with better patient survival. Through transcriptome sequencing and Me-RIP sequencing, we revealed that E2F2 and CDKN2C were the direct targets of FTO-mediated m6A modification and ZFXH3 was required for the regulation of FTO on E2F2 and CDKN2C expression. Unexpectedly, we uncovered that ZFHX3 expression was in return regulated by FTO in a m6A-dependent way. These findings establish a novel crosstalk mechanism between ZFHX3 and FTO in prostatic tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244356 | GEO | 2023/10/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

N6-methyladenosine modification is essential for prostate cancer cells

Project description:N6-methyladenosine (m6A) modification of messenger RNAs (mRNAs) is a pivotal mechanism controlling mRNA fate in cells. RNA m6A modification is regulated by the functional balance between methyltransferases and demethylases. Here we demonstrated that FTO-IT1 enhancer RNA (eRNA), a long non-coding RNA (lncRNA) transcribed from the last intron of FTO gene is significantly upregulated in CRPC and aggressive tumors compared to primary tumors. FTO-IT1 knockout by CRISPR/Cas9 almost completely blocks growth and G1-S cell cycle transition of both androgen-sensitive and castration-resistant prostate cancer cells. Meanwhile, the mRNA m6A was dramatically increased in FTO-IT knockout PCa cells and we identified FTO-IT1 as a binding partner of FTO. From m6A-seq, we unexpectedly found hypermethylated m6A associated with upregulated levels of the mRNAs for p53 signaling pathway genes in 22Rv1 prostate cancer cells. Mechanistic study showed that FTO-IT1 recruits FTO to the P53 target mRNA to promote their m6A demethylation, which leads to their degradation.

2023-07-09 | GSE189465 | GEO

A lncRNA from the FTO locus acts as an inhibitor of mRNA m6A methylation and p53 tumor suppression

Project description:The FTO gene locus has been linked to cancer and obesity through encoded N6-methyladenosine (m6A) demethylase FTO or inherited genomic variants (e.g. intronic single-nucleotide polymorphisms). Here we demonstrate that FTO-IT1, a long noncoding RNA (lncRNA) transcribed from a FTO gene intron, is upregulated during prostate cancer (PCa) progression and positively correlated with poor survival of patients with tumors only expressing wild-type p53. We show that RBM15, a mRNA/substrate binding subunit of the m6A methyltransferase complex binds and increases mRNA m6A methylation and stability of p53 transcriptional target genes; however, FTO-IT1 overexpression abolishes these effects by blocking RBM15 binding of p53 target gene mRNAs. Therapeutic targeting of FTO-IT1 restores mRNA m6A level and p53 signaling and inhibits PCa tumor growth in mice. Our study identifies FTO-IT1 lncRNA as a bono fide inhibitor of m6A methylation and p53 tumor suppression and nominates FTO-IT1 as a potential biomarker and therapeutic target of cancer.

2023-07-08 | GSE212043 | GEO

Transcriptome of control and FTO-knockdown HOC313 cells

Project description:N6-methyladenosine (m6A) modification is the major post-transcriptional modification present in mammalian mRNA. m6A controls fundamental biological processes including cell proliferation, but the molecular mechanism remains unclear. Herein, we demonstrate that the m6A demethylase fat mass and obesity-associated (FTO) controls the cell cycle by targeting cyclin D1, the key regulator required for G1 phase progression. FTO silencing suppressed cyclin D1 expression and induced G1 arrest. FTO depletion upregulated cyclin D1 m6A modification, which in turn accelerated the degradation of cyclin D1 mRNA. Importantly, m6A modification of cyclin D1 oscillates in a cell cycle-dependent manner; m6A levels were suppressed during the G1 phase and enhanced during other phases. Low m6A levels during G1 were associated with nuclear translocation of FTO from the cytosol. Furthermore, nucleocytoplasmic shuttling of FTO is regulated by Casein Kinase II-mediated phosphorylation at Thr 150 of FTO. Our results highlight the role of m6A in regulating cyclin D1 mRNA stability, and add a new layer of complexity to cell cycle regulation.

2020-03-23 | GSE133857 | GEO

Loss of the Atrial Fibrillation-related gene, Zfhx3, Results in Atrial Dilation and Arrhythmias by Disruption of Genes Essential for Cardiovascular Homeostasis

Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.

2023-06-30 | GSE229525 | GEO

FTO-dependent inhibition of ferroptosis in gastric cancer through epigenetic regulation of the HOXC8/MDM2/p53 signaling pathway

Project description:Only a few studies have attempted to explore the potential role of FTO in gastric cancer, with one focusing on mitochondrial metabolism, while others have focused on the association of FTO with cell proliferation, migration, and invasion. To date, no study has comprehensively linked FTO-dependent m6A methylation to any form of cell death. We comprehensively explore the role of FTO-mediated m6A modification in gastric cancer ferroptosis by MeRIP-seq.

2024-03-03 | GSE210623 | GEO

The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [FTO KO]

Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice

2013-06-15 | E-GEOD-47216 | biostudies-arrayexpress

Quantitative Proteomics of Mouse Liver (FTO-KO,WT) in response to DEN injection

Project description:Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.

2020-11-03 | PXD018223 | Pride

N6-methyladenosine demethylation by the fat mass and obesity-associated gene (FTO) defines tyrosine kinase inhibitor resistance in leukemia

Project description:The discovery of activating mutations in receptor tyrosine kinases (RTKs) leads to clinical testing of RTK inhibitors (TKIs). However, the rapid acquisition of resistance limits TKI effectiveness. Here we establish TKI-resistant cells that propagate in the absence of RTK signaling. Relative to sensitive cells, TKI-resistant cells display decreased N6-methyladenosine (m6A), a ubiquitous and reversible modification on RNA, but upregulated fat mass and obesity-associated gene (FTO), an m6A demethylase. Notably, the naïve leukemia cell populations are heterogeneous with respect to FTO levels. Cells with higher intrinsic and transient FTO expression demonstrate reduction of m6A methylation and TKI sensitivity with higher tumorigenic. Genetic or pharmacological dysfunction of FTO increases m6A abundance sensitizing resistant cells to TKIs. Mechanistically, FTO-mediated m6A demethylation promotes mRNA stability and protein translation rate, upregulating oncogenes that are indispensable for survival and proliferation. Our findings therefore establish a role of FTO-dependent m6A demethylation for TKI-resistance, offering a therapeutic window for incorporating m6A modulators in counteracting acquired TKI resistance.

2018-11-14 | GSE80481 | GEO

The interacted proteins of ALKBH5 and FTO identified by IP-mass

Project description:Since m6A demethylases (FTO and ALKBH5) have been reported to be involved in pre-mRNA splicing regulation, we hypothesized that dynamic m6A distribution during mRNA maturation might involve removal of m6A in internal exons by FTO or ALKBH5 accompanied by splicing factors. To explore this we performed pull-down assays coupled with protein mass spectrometry.

2022-12-09 | PXD038705 | Pride

Arabidopsis Messenger RNA N6-methyladenosine Demethylation Regulates Plant Development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification in the messenger RNA (mRNA) of all higher eukaryotes. This modification has been shown to be reversible in mammals; it is installed by a methyltransferase heterodimer complex of METTL3 and METTL14 bound with WTAP, and reversed by iron(II)- and Î±-ketoglutarate-dependent demethylases FTO and ALKBH5. This modification exhibits significant functional roles in various biological processes. The m6A modification as a RNA mark is recognized by reader proteins, such as YTH domain family proteins and HNRNPA2B1; m6A can also act as a structure switch to affect RNA-protein interactions for biological regulation. In Arabidopsis thaliana, the methyltransferase subunit MTA (the plant orthologue of human METTL3, encoded by At4g10760) was well characterized and FIP37 (the plant orthologue of human WTAP) was first identified as the interacting partner of MTA. Here we report the discovery and characterization of reversible m6A methylation mediated by AtALKBH10B (encoded by At4g02940) in A. thaliana, and noticeable roles of this RNA demethylase in affecting plant development and floral transition. Our findings reveal potential broad functions of reversible mRNA methylation in plants. m6A peaks were identified from wild type Columbia-0 and atalkbh10b-1 mutant in two biological replicates

2016-03-24 | E-GEOD-79523 | biostudies-arrayexpress

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