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A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the β-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m6A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin- and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m6A RNA methylation is a potential novel strategy for the treatment of AD.  相似文献   

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Hepatocellular carcinoma (HCC) is insidious and prone to metastasis and recurrence. Currently, no effective treatment is available for HCC. Furthermore, HCC does not respond to various radio- and chemotherapies, and the molecular mechanism of treatment resistance is unclear. Here, we found that p53 n6-methyladenosine (m6A) played a decisive role in regulating HCC sensitivity to chemotherapy via the p53 activator RG7112 and the vascular endothelial growth factor receptor inhibitor apatinib. Our results reveal that p53 activation plays a crucial role in chemotherapy-induced apoptosis and reducing cell viability. Moreover, decreasing m6A methyltransferase (e.g., methyltransferase-like 3, METTL3) expression through chemotherapeutic drug combinations reduced p53 mRNA m6A modification. p53 mRNA m6A modification blockage induced by S-adenosyl homocysteine or siRNA-mediated METTL3 inhibition enhanced HCC sensitivity to chemotherapy. Importantly, we observed that downregulation of METTL3 and upregulation of p53 expression by oral administration of chemotherapy drugs triggered apoptosis and xenograft tumor growth inhibition in nude mice. Based on these findings, we hypothesize that a METTL3–m6A–p53 axis could be a potential target in HCC therapy.

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Uncontrolled epithelial cell proliferation in the prostate transition zone and the hyper-accumulation of mesenchymal-like cells derived from the epithelial-mesenchymal transition (EMT) of prostatic epithelium are two key processes in benign prostatic hyperplasia (BPH). m6A RNA modification affects multiple cellular processes, including cell proliferation, apoptosis, and differentiation. In this study, the aberrant up-regulation of methylase METTL3 in BPH samples suggests its potential role in BPH development. Elevated m6A modification in the prostate of the BPH rat was partially reduced by METTL3 knockdown. METTL3 knockdown also partially reduced the prostatic epithelial thickness and prostate weight, significantly improved the histological features of the prostate, inhibited epithelial proliferation and EMT, and promoted apoptosis. In vitro, METTL3 knockdown decreased TGF-β-stimulated BPH-1 cell proliferation, m6A modification, and EMT, whereas promoted cell apoptosis. METTL3 increased the m6A modification of PTEN and inhibited its expression through the reading protein YTHDF2. PTEN knockdown aggravated the molecular, cellular, and pathological alterations in the prostate of BPH rats and amplified TGF-β-induced changes in BPH-1 cells. More importantly, PTEN knockdown partially abolished the improving effects of METTL3 knockdown both in vivo and in vitro. In conclusion, the level of m6A modification is elevated in BPH; the METTL3/YTHDF2/PTEN axis disturbs the balance between epithelial proliferation and apoptosis, promotes EMT, and accelerates BPH development in an m6A modification-related manner.Subject terms: Cell biology, Molecular biology  相似文献   

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N6-methyladenosine (m6A) modification acts as the most prevalent modification on eukaryotic RNA, and its function on oral squamous cell carcinoma (OSCC) is still unclear. Here, the present research aimed to explore the novel function of m6A methyltransferase KIAA1429 in OSCC. Results illustrated that KIAA1429 up-regulated in the OSCC samples and cells. Gain/loss functional assays demonstrated that KIAA1429 repressed the ferroptosis of OSCC. Moreover, KIAA1429 positively accelerated the aerobic glycolysis of OSCC, including glucose uptake, lactate production, ATP level and ECAR. Mechanistically, KIAA1429 could install the m6A modification on the PGK1 mRNA, thereby up-regulating the methylated m6A level. Moreover, m6A reader YTHDF1 recognized the m6A modification site of PGK1 mRNA and enhanced its mRNA stability. Thus, KIAA1429 promoted the OSCC aerobic glycolysis and inhibited the ferroptosis of OSCC through YTHDF1-mediated PGK1 mRNA stability. Taken together, these findings reveal a novel insight for KIAA1429 on OSCC via m6A-dependent manner.  相似文献   

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胡滨滨  张明 《生物信息学》2022,20(2):124-135
为探讨RNA m6A甲基化调节因子在肺腺癌中的作用,从TCGA数据库下载肺腺癌患者的RNA表达数据和临床数据。通过limma软件包分析12种m6A调节剂的表达情况。使用Pheatmap、vioplot和corrplot软件包生成热图、小提琴图和表达相关图。采用Kaplan-Meier方法分别计算肺腺癌中12种RNA m6A调节因子的生存曲线。使用Cox回归和Kaplan-Meier方法分析TCGA肺腺癌患者的总体存活相关的临床病理学特征。最后用Kruskal(KS)检验和logistic回归分析临床病理学特征与HNRNPC表达的关系。 在肺腺癌的TCGA队列中,发现HNRNPC、WTAP、YTHDF3、FTO、ZC3H13、METTL14、METTL3、YTHDF1、YTHDF2这些基因是差异表达的。Kaplan-Meier生存分析显示,在这些差异表达的基因中仅仅HNRNPC和YTHDF2的表达与生存显著相关。然后,通过多因素Cox回归结果表明HNRNPC的表达在肺腺癌TCGA队列中是个独立危险因素。最后,HNRNPC在肺腺癌中的表达与临床分期(IV vs I, OR=3.692 308)和组织浸润(T2 vs T1, OR=1.776 471;T4 vs T1, OR=6.303 03)显著相关(所有p<0.05)。 结论认为HNRNPC可能作为肺腺癌的独立的预后因子。  相似文献   

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Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl4)-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl4-induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl4-induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 (Ptgs2) and lipoxygenases (LOXs) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system XC to prevent CCl4-induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.Subject terms: Hepatotoxicity, Experimental models of disease

Schematic diagram of the protective effect of MSC-derived exosomes on maintaining SLC7A11 function during ferroptosis involved in CCl4-induced ALI.  相似文献   

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Background: Bladder cancer (BC) is one of the most common malignant urological cancer in the world. Because of its characteristic of easy-recurrence and muscle-invasive, advances in our genetic understanding of bladder cancer should be translated into prognostic indicators.Methods: We investigated 16 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas (HPA) database. The expression profile, clinical application as well as prognostic value of these genes in UC were investigated. Moreover, we further explored the correlation between RNA methylation genes and biological functions, pathways and immune status.Results: Five m6A-related genes (HNRNPC, YTHDF2, YTHDF1, HNRNPA2B1, METTL3) up-regulated in UC tissues, while three regulators (ZC3H13, METTL16, FTO) down-regulated in UC. FTO and YTHDF2 show biomarker potential for the prognosis of UC patients. In addition, these identified genes may related with essential functions and core molecular pathways.Conclusions: Our research shows that two m6A RNA methylation regulators can serve as reliable prognostic biomarkers of UC, which might be exerted as potential targets of therapeutic strategies.  相似文献   

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The objective of this study was to explore the role of ferroptosis in the formation of calcium oxalate (CaOx) kidney stones and the regulatory mechanism of the ankyrin repeat domain 1 (ANKRD1) gene. The study found that the Nrf2/HO-1 and p53/SLC7A11 signaling pathways were activated in the kidney stone model group, and the expression of the ferroptosis marker proteins SLC7A11 and GPX4 was significantly reduced, while the expression of ACSL4 was significantly increased. The expression of the iron transport-related proteins CP and TF increased significantly, and Fe2+ accumulated in the cell. The expression of HMGB1 increased significantly. In addition, the level of intracellular oxidative stress was increased. The gene with the most significant difference caused by CaOx crystals in HK-2 cells was ANKRD1. Silencing or overexpression of ANKRD1 by lentiviral infection technology regulated the expression of the p53/SLC7A11 signaling pathway, which regulated the ferroptosis induced by CaOx crystals. In conclusion, CaOx crystals can mediate ferroptosis through the Nrf2/HO-1 and p53/SLC7A11 pathways, thereby weakening the resistance of HK-2 cells to oxidative stress and other unfavorable factors, enhancing cell damage, and increasing crystal adhesion and CaOx crystal deposition in the kidney. ANKRD1 participates in the formation and development of CaOx kidney stones by activating ferroptosis mediated by the p53/SLC7A11 pathway.  相似文献   

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N6‐methyladenosine (m6A) is a highly dynamic RNA modification that has recently emerged as a key regulator of gene expression. While many m6A modifications are installed by the METTL3–METTL14 complex, others appear to be introduced independently, implying that additional human m6A methyltransferases remain to be identified. Using crosslinking and analysis of cDNA (CRAC), we reveal that the putative human m6A “writer” protein METTL16 binds to the U6 snRNA and other ncRNAs as well as numerous lncRNAs and pre‐mRNAs. We demonstrate that METTL16 is responsible for N6‐methylation of A43 of the U6 snRNA and identify the early U6 biogenesis factors La, LARP7 and the methylphosphate capping enzyme MEPCE as METTL16 interaction partners. Interestingly, A43 lies within an essential ACAGAGA box of U6 that base pairs with 5′ splice sites of pre‐mRNAs during splicing, suggesting that METTL16‐mediated modification of this site plays an important role in splicing regulation. The identification of METTL16 as an active m6A methyltransferase in human cells expands our understanding of the mechanisms by which the m6A landscape is installed on cellular RNAs.  相似文献   

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Mitochondrial biogenesis and energy metabolism are essential for regulating the inflammatory state of monocytes. This state is partially controlled by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a coactivator that regulates mitochondrial biogenesis and energy metabolism. Disruption of these processes can also contribute to the initiation of chronic inflammatory diseases, such as pulmonary fibrosis, atherosclerosis, and rheumatoid arthritis. Methyltransferase-like 3 (METTL3)-dependent N6-methyladenosine (m6A) methylation has recently been shown to regulate a variety of inflammatory processes. However, the role of m6A mRNA methylation in affecting mitochondrial metabolism in monocytes under inflammation is unclear, nor is there an established relationship between m6A methylation and PGC-1α. In this study, we identified a novel mechanism by which METTL3 acts during oxidized low-density lipoprotein (oxLDL)-induced monocyte inflammation, where METTL3 and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) cooperatively modify PGC-1α mRNA, mediating its degradation, decreasing PGC-1α protein levels, and thereby enhancing the inflammatory response. METTL3 coordinated with YTHDF2 to suppress the expression of PGC-1α, as well as that of cytochrome c (CYCS) and NADH:ubiquinone oxidoreductase subunit C2 (NDUFC2) and reduced ATP production and oxygen consumption rate (OCR). This subsequently increased the accumulation of cellular and mitochondrial reactive oxygen species (ROS) and the levels of proinflammatory cytokines in inflammatory monocytes. These data may provide new insights into the role of METTL3-dependent m6A modification of PGC-1α mRNA in the monocyte inflammation response. These data also contribute to a more comprehensive understanding of the pathogenesis of monocyte-macrophage inflammation-associated diseases, such as pulmonary fibrosis, atherosclerosis, and rheumatoid arthritis.  相似文献   

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Chemoresistance represents a major obstacle to the treatment of human cancers. Increased DNA repair capacity is one of the important mechanisms underlying chemoresistance. In silico analysis indicated that YTHDF1, an m6A binding protein, is a putative tumor promoter in breast cancer. Loss of function studies further showed that YTHDF1 promotes breast cancer cell growth in vitro and in vivo. YTHDF1 facilitates S-phase entry, DNA replication and DNA damage repair, and accordingly YTHDF1 knockdown sensitizes breast cancer cells to Adriamycin and Cisplatin as well as Olaparib, a PARP inhibitor. E2F8 is a target molecule by YTHDF1 which modulates E2F8 mRNA stability and DNA damage repair in a METTL14-dependent manner. These data demonstrate that YTHDF1 has a tumor-promoting role in breast cancer, and is a novel target to overcome chemoresistance.Subject terms: Breast cancer, Breast cancer  相似文献   

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Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m6A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m6A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m6A modification were measured by MTT assay, flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m6A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m6A inhibitor). METTL3 overexpression enhanced m6A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo. HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF.  相似文献   

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m6A methylation is the most abundant and reversible chemical modification on mRNA with approximately one-fourth of eukaryotic mRNAs harboring at least one m6A-modified base. The recruitment of the mRNA m6A methyltransferase writer complex to phase-separated nuclear speckles is likely to be crucial in its regulation; however, control over the activity of the complex remains unclear. Supported by our observation that a core catalytic subunit of the methyltransferase complex, METTL3, is endogenously colocalized within nuclear speckles as well as in noncolocalized puncta, we tracked the components of the complex with a Cry2-METTL3 fusion construct to disentangle key domains and interactions necessary for the phase separation of METTL3. METTL3 is capable of self-interaction and likely provides the multivalency to drive condensation. Condensates in cells necessarily contain myriad components, each with partition coefficients that establish an entropic barrier that can regulate entry into the condensate. In this regard, we found that, in contrast to the constitutive binding of METTL14 to METTL3 in both the diffuse and the dense phase, WTAP only interacts with METTL3 in dense phase and thereby distinguishes METTL3/METTL14 single complexes in the dilute phase from METTL3/METTL14 multicomponent condensates. Finally, control over METTL3/METTL14 condensation is determined by its small molecule cofactor, S-adenosylmethionine (SAM), which regulates conformations of two gate loops, and some cancer-associated mutations near gate loops can impair METTL3 condensation. Therefore, the link between SAM binding and the control of writer complex phase state suggests that the regulation of its phase state is a potentially critical facet of its functional regulation.

Approximately one-fourth of eukaryotic mRNAs harbor at least one m6A-modified base, but how is this regulated? This study shows that cells can use liquid-liquid phase separation to regulate dynamic assembly of the mRNA m6A methyltransferase complex (METTL3/METTL14/WTAP), with stoichiometries that depend on condensate partitioning in a substrate binding-dependent manner.  相似文献   

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