METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Cancer Cell International, Journal Year: 2022, Volume and Issue: 22(1)

Published: Jan. 7, 2022

Abstract Background N6-methyladenosine (m 6 A) has emerged as a significant regulator of the progress various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored biological function and underlying mechanism methyltransferase-like 3 (METTL3), main catalyst m A, LUAD progression. Methods The expression METTL3, YTHDF1 SLC7A11 were detected by immunochemistry or/and online datasets patients. effects METTL3 on cell proliferation, apoptosis ferroptosis assessed through vitro loss-and gain-of-function experiments. vivo effect tumorigenesis was evaluated using xenograft mouse model. MeRIP-seq, RNA immunoprecipitation stability assay conducted to explore molecular LUAD. Results results showed that A level, well methylase both significantly elevated patients cancer cells. Functionally, found could promote proliferation inhibit different models, while knockdown suppressed growth cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), subunit system Xc − , identified direct target mRNA-seq MeRIP-seq. METTL3-mediated modification stabilize mRNA translation, thus promoting inhibiting ferroptosis, novel form programmed death. Additionally, demonstrated YTHDF1, reader, recruited enhance modification. Moreover, positively correlated with tissues. Conclusions These findings reinforced oncogenic progression revealed correlation ferroptosis; these also indicate is promising diagnosis therapy.

Language: Английский

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m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(5)

Published: May 21, 2022

Abstract Exploring the epigenetic regulation mechanism of colorectal cancer (CRC) from perspective N6-methyladenosine (m6A) modification may provide a new target for tumor therapy. Analysis using high-throughput RNA-seq profile TCGA found that gene expression Methyltransferase-like 3 (METTL3) was significantly upregulated among 20 m6A binding proteins in CRC, which also validated CRC tissues and cell lines. Moreover, transcriptome sequencing METTL3 knockdown cells CRISPR/Cas9 editing suggested EphA2 VEGFA were differential expression, enriched vasculature development, PI3K/AKT ERK1/2 signal pathway through functional enrichment analysis. The results vitro revealed as “writers” participates methylation VEGFA, recognized by “readers”, insulin-like growth factor 2 mRNA protein 2/3 (IGF2BP2/3), to prevent their degradation. In addition, targeted via different IGF2BP-dependent mechanisms promote vasculogenic mimicry (VM) formation PI3K/AKT/mTOR signaling CRC. study suggests intervention with m6A-binding (METTL3 IGF2BP2/3) potential diagnostic or prognostic VM-based anti-metastasis drugs

Language: Английский

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The roles and mechanism of m6A RNA methylation regulators in cancer immunity

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 163, P. 114839 - 114839

Published: May 8, 2023

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented immune checkpoint blocking has increasingly become an effective cancer treatment, increasing shreds evidence show that RNA methylation affects immunity various cancers. Until now, there have been few reviews about role mechanism immunity. Here, we first summarized regulation regulators on expression target messenger RNAs (mRNA) their corresponding roles inflammation, response, process cells. Meanwhile, described mechanisms tumor microenvironment response affecting stability non-coding (ncRNA). Moreover, also discussed or its which might used as predictor diagnosis prognosis, shed light potentiality therapeutic targets

Language: Английский

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The role of m6A methylation in therapy resistance in cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: June 1, 2023

Cancer therapy resistance is the main cause of cancer treatment failure. The mechanism a hot topic in epigenetics. As one most common RNA modifications, N6-methyladenosine (m6A) involved various processes metabolism, such as stability, splicing, transcription, translation, and degradation. A large number studies have shown that m6A methylation regulates proliferation invasion cells, but role unclear. In this review, we summarized research progress related to regulating cancers.

Language: Английский

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RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Jan. 3, 2022

Lymph node metastasis is the main cause of poor prognosis head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification an emerging epigenetic regulatory mechanism for gene expression, as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression metastasis. However, not much currently known about functional roles HNSCC, whether regulates lymphatic through HNSCC remains to be determined.The expression overall survival (OS) probability m6A-related regulators were analyzed with The Cancer Genome Atlas (TCGA) dataset GEPIA website tool, respectively. levels measured tissues normal adjacent tissues. To study effects on cell vitro vivo, gain- loss- function methods employed. RIP, MeRIP, luciferase reporter mRNA stability assays performed explore HNSCC.We investigated 20 discovered that only overexpression was associated OS independent prognostic factor Additionally, we demonstrated overexpressed tissues, significantly correlated prognosis. Functional studies have shown promotes both migration well invasion via epithelial-mesenchymal transition (EMT) process vitro, knockdown inhibited lymphangiogenesis vivo. Mechanistic investigations revealed Slug, key EMT-related transcriptional factor, direct target IGF2BP2, essential IGF2BP2-regulated EMT HNSCC. Furthermore, recognizes binds site coding sequence (CDS) region Slug its stability.Collectively, our uncovers oncogenic role potential which serves reader, controlling suggesting may act therapeutic biomarker patients

Language: Английский

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Epigenetic modification of m6A regulator proteins in cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: June 30, 2023

Divergent N6-methyladenosine (m6A) modifications are dynamic and reversible posttranscriptional RNA that mediated by m6A regulators or methylation regulators, i.e., methyltransferases ("writers"), demethylases ("erasers"), m6A-binding proteins ("readers"). Aberrant associated with cancer occurrence, development, progression, prognosis. Numerous studies have established aberrant function as either tumor suppressors oncogenes in multiple types. However, the functions mechanisms of remain largely elusive should be explored. Emerging suggest can modulated epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, lactylation via noncoding action, cancer. This review summarizes current roles The for modification genesis segregated. will improve understanding regulatory regulators.

Language: Английский

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Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 73, P. 101063 - 101063

Published: Feb. 1, 2024

This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance liver metastasis breast cancer.

Language: Английский

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Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Feb. 3, 2022

Abstract RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N 6 -methyladenine (m A) most abundant modification. Methyltransferase-like 14 (METTL14) central component m A methylated transferase complex, which involved dynamic reversible process METTL14 acts as both an oncogene tumor suppressor gene to regulate occurrence development various cancers. The level induced by related tumorigenesis, proliferation, metastasis, invasion. To date, molecular mechanism malignant tumors has not been fully studied. In this paper, we systematically summarize latest research progress on new biomarker for cancer diagnosis function human discuss potential clinical application. This study aims provide ideas targeted therapy improved prognoses

Language: Английский

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Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 4, 2022

Background AlkB homolog 5 (ALKBH5) is a N 6 -methyladenosine (m A) demethylase associated with the development, growth, and progression of multiple cancer types. However, biological role ALKBH5 has not been investigated in pan-cancer datasets. Therefore, this study, comprehensive bioinformatics analysis datasets was performed to determine mechanisms through which regulates tumorigenesis. Methods Online websites databases such as NCBI, UCSC, CCLE, HPA, TIMER2, GEPIA2, cBioPortal, UALCAN, STRING, SangerBox, ImmuCellAl, xCell, GenePattern were used extract data cancers. The patient analyzed relationship between expression, genetic alterations, methylation status, tumor immunity. Targetscan, miRWalk, miRDB, miRabel, LncBase Cytoscape tool identify microRNAs (miRNAs) long non-coding RNAs (lncRNAs) that regulate expression construct lncRNA-miRNA-ALKBH5 network. In vitro CCK-8, wound healing, Transwell M2 macrophage infiltration assays well vivo xenograft animal experiments functions glioma cells. Results showed upregulated several solid tumors. significantly correlated prognosis patients. Genetic alterations including duplications deep mutations gene identified Alterations prognosis. GO KEGG enrichment analyses ALKBH5-related genes enriched inflammatory, metabolic, immune signaling pathways glioma. checkpoint (ICP) genes, influenced sensitivity immunotherapy. We constructed lncRNA-miRNA network development progression. promoted proliferation, migration, invasion cells recruited Conclusions overexpressed types cancers regulation tumor-infiltration Our study shows promising prognostic immunotherapeutic biomarker some malignant

Language: Английский

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The RNA m6A writer WTAP in diseases: structure, roles, and mechanisms

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(10)

Published: Oct. 7, 2022

N6-methyladenosine (m6A) is a widely investigated RNA modification in studies on the "epigenetic regulation" of mRNAs that ubiquitously present eukaryotes. Abnormal changes m6A levels are closely related to regulation metabolism, heat shock stress, tumor occurrence, and development. modifications catalyzed by writer complex, which contains methyltransferase-like 3 (METTL3), 14 (METTL14), Wilms 1-associated protein (WTAP), other proteins with methyltransferase (MTase) capability, such as RNA-binding motif 15 (RBM15), KIAA1429 zinc finger CCCH-type containing 13 (ZC3H13). Although METTL3 main catalytic subunit, WTAP regulatory subunit whose function recruit complex target mRNA. Specifically, required for accumulation METTL14 nuclear speckles. In this paper, we briefly introduce molecular mechanism modification. Then, focus WTAP, component its structure, localization, physiological functions. Finally, describe roles mechanisms cancer.

Language: Английский

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