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A lncRNA from the FTO locus acts as an inhibitor of the m6A writer complex and p53 tumor suppression signaling

ABSTRACT: control RNA and FTO-IT1 RNA and their interacting proteins were pulled down by biotin-streptavidin beads to see the interacting protein of FTO-IT1 RNA.

INSTRUMENT(S): 6410 Triple Quadrupole LC/MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: 嘉农张

LAB HEAD: haojie huang

PROVIDER: PXD041053 | Pride | 2024-08-09

REPOSITORIES: Pride

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	67467_65949.mzXML	Mzxml
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Publications

A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling.

Zhang Jianong J Wei Jiangbo J Sun Rui R Sheng Haoyue H Yin Kai K Pan Yunqian Y Jimenez Rafael R Chen Sujun S Cui Xiao-Long XL Zou Zhongyu Z Yue Zhiying Z Emch Michael J MJ Hawse John R JR Wang Liguo L He Housheng Hansen HH Xia Shujie S Han Bangmin B He Chuan C Huang Haojie H

Molecular cell 20230720 15

N6-methyladenosine (m6A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m6A demethylases such as FTO play important roles in regulating mRNA stability, splicing, and translation. Here, we demonstrate that FTO-IT1 long noncoding RNA (lncRNA) was upregulated and positively correlated with poor survival of patients with wild-type p53-expressing prostate cancer (PCa). m6A RIP-seq analysis revealed that FTO-IT1 knockout in ...[more]

PMID: 37478845

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Role of circNFKB1 in cartilage degeneration of knee osteoarthritis and its mechanism

Project description:Circular RNAs (circRNAs) are covalently closed single-stranded RNA molecules produced by reverse splicing of the precursor mRNAs of thousands of gene exons in eukaryotes. Some circRNAs play potentially important roles at the molecular level through different modes of action in physiological and pathological conditions. In recent years, it has been found that differentially expressed circRNAs are present in chondrocyte degeneration in OA and are able to modulate the inflammatory response in chondrocyte degeneration. However, the molecular mechanisms of how circRNAs regulate the inflammatory response during chondrogenic degeneration in OA have not been adequately studied. Are there other circRNAs involved in regulating the inflammatory response during knee OA chondrocyte degeneration and are there other molecular mechanisms by which circRNAs regulate chondrocyte degeneration? These scientific questions deserve relevant studies.

2022-10-15 | PXD033469 | Pride

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

Utilization of Stability-based Proteomics for the Investigation of Structured RNA-protein Interactions

Project description:The stability of proteins from rates of oxidation (SPROX), thermal protein profiling (TPP) methods as well as triple helix pulldowns with LC-MS/MS readouts are used to identify the protein targets of three RNA ligands, the MALAT1 triple helix (TH), a viral stem loop (SL), and an unstructured RNA (PolyU) in LNCaP nuclear lysate. This work establishes a novel platform for the global discovery and interrogation of RNA-protein interactions that is generalizable to numerous biological contexts and RNA targets.

2024-01-31 | PXD043878 | Pride

TUBA1C: a new potential target of LncRNA EGFR-AS1 promotes gastric cancer progression

Project description:Background: The lack of obvious symptoms of early gastric cancer (GC) as well as the absence of sensitive and specific biomarkers results in poor clinical outcomes. Tubulin is currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders, however, its mechanism of action in gastric cancer is still unclear. Tubulin alpha-1C(TUBA1C) is a subtype of α-tubulin, high TUBA1C expression has been shown to be closely related to a poor prognosis in in various cancers,this study, for the first time, revealed the mechanism of TUBA1C promotes malignant progression of gastric cancer in vitro and in vivo. Methods: The expression of lncRNA EGFR-AS1 was detected in human GC cell lines by qRT–PCR. Mass spectrometry experiments following RNA pulldown assays found that EGFR-AS1 directly binds to TUBA1C, the CCK8, EdU, transwell, wound-healing, cell cycle assays and animal experiments were conducted to investigate the function of TUBA1C in GC. Combined with bioinformatics analyses, reveal interaction between Ki-67, E2F1, PCNA and TUBA1C by western blot. Rescue experiments furtherly demonstrated the relationship of EGFR-AS1and TUBA1C. Results: TUBA1C was proved to be a direct target of EGFR-AS1, TUBA1C promotes gastric cancer proliferation, migration and invasion by accelerating the progression of the cell cycle from the G1 phase to the S phase and activating the expression of oncogenes: Ki-67,E2F1 and PCNA. Conclusions: TUBA1C is a new potential target of LncRNA EGFR-AS1 promotes gastric cancer progression and could be a novel biomarker and therapeutic target for GC.

2023-05-10 | PXD040199 | Pride

m6A IP sequencing analysis of m6A mRNA methylation regulation by FTO in melanoma cells

Project description:N6-methyladenosine (m6A) RNA methylation is the most abundant internal chemical modifications in eukaryotic messenger RNA (mRNA) as well as long non-coding RNA (lncRNA). Recently, m6A RNA methylation research was revived by the discovery of the fat mass- and obesity-associated protein (FTO) as the first RNA demethylase, implicating that m6A RNA methylation is a reversible and dynamic modification and may have critical biological functions. Emerging evidence has shown that m6A modifications in mRNAs and lncRNAs play crucial roles in regulating RNA fate and function in biological processes in the past several years. As the first identified RNA demethylase that regulates the demethylation of target mRNAs, FTO has been reported to play an oncogenic role in leukemia and glioblastoma stem cells. To identify the target genes of FTO in melanoma cells, we used m6A IP seq coupled with RNA seq to determine the potential demethylation and gene targets across the whole transcriptome for FTO, and identified more than 1,000 genes.

2019-05-06 | GSE112902 | GEO

Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in Cell Nucleus and Cytoplasm

Project description:FTO, the first RNA demethylase discovered, mediates the demethylation of N6-methyladenosine (m6A), installed internally on messenger RNA, and N6,2′-O-dimethyladenosine (m6Am), occurring at the +1 position from the 5’ cap. Despite extensive recent research on FTO, its physiological impact on cellular processes has yet to be fully elucidated. Here, we demonstrate that the cellular distribution of FTO is distinct among different cell lines, which critically affects the access of FTO to different RNA substrates. FTO binds multiple RNA substrates, including mRNA, U6 RNA, and tRNA. It mainly targets internal m6A when located in the cell nucleus and preferentially demethylates m6Am when residing in the cytoplasm. The expression levels of transcripts containing internal m6A are associated with the alteration of the FTO more so than transcripts containing m6Am. We also discover that N1-methyladenosine (m1A) in tRNA is a main substrate of FTO, with the FTO-catalyzed demethylation of target tRNAs repressing protein synthesis. Collectively, FTO-mediated RNA demethylation affects both mRNA level and translation through distinct pathways.

2018-09-14 | GSE106395 | GEO

Mass spectrometry approach to identify mitochondrial poly(A) RNA interacting proteins

Project description:To identify mitochondrial RNA-interacting proteins, we developed three related mass spectrometry based methods. In the first method, called mitochondrial crosslinking (MXL), mitochondria of 4-thiouridine labelled cells were isolated, exposed to UV-light and poly(A) RNA was isolated. In the second method, called whole cell crosslinking (WCXL), 4-thiouridine labelled cells were first exposed to UV-light, subsequently mitochondria were isolated followed by a poly(A) RNA extraction. The third method, called ethidium bromide whole cell crosslinking (WCXL_EtBr), is exactly the same as the WCXL method, but the cells are cultured with ethidium bromide to reduce the amount of mitochondrial RNA. In all methods poly(A) RNA was degraded and proteins in the sample were digested and identified using mass spectrometry.

2019-10-15 | PXD014957 | Pride

FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA (mRNA). It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein (FTO). Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.

2022-05-05 | GSE151780 | GEO

m6A 'writer' KIAA1429 regulates the proliferation and migration of endothelial cells in atherosclerosis.

Project description:Increasing evidences have illustrated the important role of N6-methyladenosine (m6A) in atherosclerosis (AS). However, the role of m6A modification in AS pathophysiological process is still unknown. Here, the present work tried to investigate the expression and function of m6A methyltransferase KIAA1429 in AS pathology and explored its undergoing m6A-dependent molecular mechanism. Results indicated that KIAA1429 remarkedly up-regulated in oxidative low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). KIAA1429 over-expression inhibited the proliferation/migration in ox-LDL-treated HUVECs, while, KIAA1429 knockdown up-regulated the proliferation and migration. Mechanistically, via m6A modification sites binding, ROCK2 mRNA was post-transcriptionally upregulated by KIAA1429 in response to Actinomycin D. Collectively, our study demonstrated the regulation of KIAA1429 on ox-LDL-induced HUVECs via m6A/ROCK2 pathway. These findings provide new insights for m6A-mediated epigenetics in AS.

| S-EPMC9734602 | biostudies-literature

m6A alterations through FTO in breast cancer [RNA-seq]

Project description:Our understanding of posttranscriptional modifications that decorate RNA, a regulatory layer positioned between DNA and proteins, is in its infancy. N6-methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs that is installed and erased by m6A methyltransferases and demethylases. The importance of these enzymes in cancer is rapidly emerging, yet information of their specific mode of actions during disease progression remain largely unknown. In the present study, we report that the m6A RNA demethylase FTO controls EMT and invasion in cancer through regulation of the Wnt pathway. We find that loss of FTO, in contrast to acute myeloid leukemia, is frequent in many cancer types, including breast and prostate cancers. Knockdown of FTO promotes tumor progression – specifically migration and invasion – in breast and prostate cancer cells. Furthermore, implantation of these cells accelerates tumor progression in recipient mice in vivo. In these tumors, FTO depletion leads to m6A-dependent activation of Wnt signaling, which drives an enhanced EMT program and invasion, thus leading to poor clinical outcome. However, loss of FTO also sensitizes cancers cells to Wnt inhibition, offering a rationale for the therapeutic targeting of Wnt for cancer patients with low FTO levels. Together, our work reveals FTO as a novel regulator of EMT and an unexpected mechanism by which Wnt signals are dysregulated in tumors, providing a rationale to stratify cancer patients treated with Wnt inhibitor. These data uncover a previously unrecognized relationship between RNA modification and EMT in cancer.

2021-01-11 | GSE128581 | GEO