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N6-methyladenosine modification is essential for prostate cancer cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189465 | GEO | 2023/07/09

REPOSITORIES: GEO

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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

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

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2020-03-23 | GSE133857 | GEO

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

Project description: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.

2023-10-31 | GSE244356 | GEO

Transcriptome-wide m6A methylome analysis uncovered the changes of m6A modification in oral pre-malignant cells compared with normal oral epithelial cells

Project description:As the most common post-transcriptional RNA modification, m6A methylation extensively regulates the structure and function of RNA. The dynamic and reversible modification of m6A is coordinated by m6A writers and erasers. m6A reader proteins recognize m6A modification on RNA, mediating different downstream biological functions. mRNA m6A modification and its corresponding regulators play an important role in cancers, but its characteristics in the precancerous stage are still unclear. In this study, we used oral precancerous DOK cells as a model to explore the characteristics of transcriptome-wide m6A modification and major m6A regulator expression in the precancerous stage compared with normal oral epithelial cell HOEC and oral cancer cell SCC-9 through MeRIP-seq and RT-PCR. Compared with HOEC cells, we found 1180 hyper-methylated and 1606 hypo-methylated m6A peaks and 354 differentially expressed mRNAs with differential m6A peaks in DOK cells. Although the change of m6A modification in DOK cells was less than that in SCC-9 cells, mRNAs with differential m6A in both cell lines were enriched into many identical GO terms and KEGG pathways. Among the 20 known m6A regulatory genes, FTO, ALKBH5, METTL3 and VIRMA were slightly upregulated or downregulated in DOK cells, but the expression of 10 genes such as METTL14/16, FTO and IGF2BP2/3 changed significantly in SCC-9 cells. Our data suggest that precancerous cells showed, to some extent, changes of m6A modification. Identifying some key m6A targets and corresponding regulators in precancerous stage may provide potential intervention targets for the prevention of cancer development through epigenetic modification in the future.

2022-09-21 | GSE213714 | GEO

Combined analysis of ribo-seq and rna-seq reveals that Mettl3 regulates embryonic cerebral cortex development in mice by controlling the proliferation and differentiation of neural progenitor cells

Project description:N6-methyladenosine (m6A) is the most important internal messenger RNA (mRNA) modification in mammals. The role of Mettl3, the core component of methyltransferase, and Fto, the demethylase, has not been revealed in the embryonic development of the cerebral cortex in mice. We constructed the conditional knockout of Mettl3 and Fto in the cerebral cortex of mice. We found that Mettl3 deletion causes cell cycle extension of progenitors and massive proliferation of intermediate progenitors at E15.5, which lead to a fold structure of cortex, while Fto deletion hardly altered cell numbers or morphology. Meanwhile, both transcriptome sequence (RNA-Seq) and ribosome profiling (Ribo-Seq) of Mettl3-deleted cortex mRNAs in E15.5 revealed that the differential genes were enriched in cell differentiation, neurogenesis, neuron differentiation, cell proliferation, and cell cycle. Moreover, deleted Mettl3 but not Fto significantly upregulated Ythdf1 and Ythdf2, which caused a substantial change in gene translation efficiency. Our findings indicate cortex m6A represents a novel layer of complexity in gene expression regulation and provide a new mechanism of precisely programmed RNA maturation.

2021-01-04 | GSE154992 | GEO

Coordination of mRNA and tRNA methylations by TRMT10A

Project description:The post-transcriptional modification of mRNA and tRNA provides an additional layer of regulatory complexity during gene expression. TRMT10A is a tRNA methyltransferase that installs N1-methylguanosine (m1G), while FTO performs demethylation on N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) in mRNA. We find that this tRNA methyltransferase TRMT10A interacts with mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. Strikingly, depletion of TRMT10A not only led to decreased m1G in tRNA but also significantly increased m6A levels in mRNA. CLIP-seq results showed that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by specific m6A reader. Furthermore, transcripts with increased m6A upon TRMT10A ablation contain an overrepresentation of m1G9-containing tRNAs codons read by tRNAGln(TTG), tRNAArg(CCG), and tRNAThr(CGT). These findings collectively reveal the presence of coordinated mRNA and tRNA modifications and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes.

2020-04-22 | GSE146207 | GEO

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

2013-06-15 | E-GEOD-47215 | biostudies-arrayexpress

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

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