Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA932911 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23375755_1.fastq.gz | Fastqsanger.gz | |||
| SRR23375755_2.fastq.gz | Fastqsanger.gz | |||
| SRR23375756_1.fastq.gz | Fastqsanger.gz | |||
| SRR23375756_2.fastq.gz | Fastqsanger.gz | |||
| SRR23375757_1.fastq.gz | Fastqsanger.gz |
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Project description:Alternative polyadenylation (APA) serves as a critical mechanism for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3′ untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3′ UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation “writer” catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic “eraser”. Clinically, elevated LDHA and NUDT21 levels correlate with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.
2025-05-12 | GSE284372 | GEO
Project description:To investigate the targets of METTL16-induced m6A modification, we established AGS lines in which METTL16 has been knocked down by shRNA.
2023-10-05 | GSE224890 | GEO
Project description:Cuproptosis, a recently defined copper-dependent cell death, remains largely unexplored in tumor therapies, particularly in breast cancer. Our study demonstrates that triple-negative breast cancer (TNBC) bears a relative elevated copper levels and exhibit resistance to cuproptosis. Mechanistically, cooper activates AKT1 signaling pathway, which inhibits cuproptosis by directly phosphorylating ferredoxin-1 (FDX1), a key regulator involved in cuproptosis. AKT1-mediated FDX1 phosphorylation abrogates FDX1-induced cuproptosis and aerobic respiration, accompanied by promoting glycolysis. Consequently, combination of AKT1 inhibitors MK2206 and the copper ionophore elesclomol (ES) synergistically inhibits TNBC tumorigenesis both in vitro and in vivo. In summary, our findings uncover a critical mechanism underlying TNBC resistance to cuproptosis and propose a potential therapeutic approach for TNBC.
2025-05-07 | PXD058176 | Pride
Project description:Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore- elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.
| S-EPMC10589265 | biostudies-literature
Project description:NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance
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Project description:METTL16 belongs to methyltransferase like (METTL) family and could install m6A marks on its substrates. Here, we uncover a tumor-promoting role of METTL16 in AML and LSC self-renewal. To explore the mechanism underlying the oncogenic function of METTL16 in AML, we performed m6A-seq and RNA-seq. Via integrated analysis of m6A-seq data and RNA-seq data, we identified two bona fide targets of METTL16, BCAT1 and BCAT2. METTL16 functions as an m6A methyltransferase to regulate expression of BCAT1 and BCAT2, which contribute to reprogramming of BCAA metabolism.
2023-01-12 | GSE189995 | GEO
Project description:Maintenance of the intracellular levels of the methyl donor S-adenosylmethionine (SAM) is essential for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of MAT2A, which encodes the only SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which in turn promotes MAT2A splicing. Interestingly, human and S. pombe METTL16 methylate the U6 spliceosomal snRNA at a sequence identical to hp1. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.
2017-05-18 | GSE90914 | GEO
Project description:The RNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of vertebrate embryogenesis and malignancies. However, its functions and underlying molecular mechanisms in the expansion of hematopoietic stem and progenitor cells (HSPCs) during early embryonic development remain elusive. Here we show that Mettl16, an RNA methyltransferase identified recently, is specifically required for HSPC expansion during zebrafish early embryonic development in an m6A-dependent manner. In mettl16 deficient embryos, HSPCs exhibit defective proliferation capacity due to G0/G1 arrest. Mechanistically, HSPC proliferation is blocked by impaired methyltransferase function of Mettl16 in vivo. We identify cell cycle gene mybl2b as a novel direct m6A target of Mettl16, and Mettl16 deficiency destabilizes mybl2b mRNA, which is mediated by m6A reader Igf2bp1. Moreover, we revealed that the METTL16-m6A-MYBL2-IGF2BP1 signaling axis in G1/S progression is conserved in humans. Collectively, our findings demonstrate the critical function of m6A modification deposited by Mettl16 in HSPC expansion during early embryonic development.
2024-03-04 | GSE225136 | GEO
Project description:METTL16 belong to methyltransferase like (METTL) family and possesses the ability to deposit N6-methyladenosine (m6A) in mRNA. We have conducted m6A-seq with poly(A) RNAs isolated from the whole HEK293T cells upon METTL16 knockdown to identify the transcripts with hypo m6A peaks after METTL16 knockdown, and also conducted RIP-seq with HEK293T cells to determine the METTL16-bound transcripts. However, we found that the transcripts with hypo m6A peaks upon METTL16 knockdown only account for a small proportion of METTL16-bound transcripts. We suppose one of the possibility reasons might be due to spatiotemporal installation of m6A. To support our hypothesis, we performed additional m6A seq with nascent RNA and nuclear poly(A) RNA isolated from HEK293T cells with METTL16 knockdown.
2021-10-28 | GSE156795 | GEO
Project description:Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M6A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease. The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction. METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody. METTL16 may affect the expression of SLC5A3 by changing its m6A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.
| S-EPMC11293636 | biostudies-literature