Targeting the RNA m6A modification for cancer immunotherapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: March 16, 2022

Abstract N 6 -methyladenosine (m A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription translation programs that promote cancer occurrence progression. Although defective gene regulation resulting from m A often affects oncogenic tumor-suppressing networks, can also modulate tumor immunogenicity immune cells involved in anti-tumor responses. Understanding this counterintuitive concept aid design new drugs target to potentially improve outcomes immunotherapies. Here, we provide an up-to-date comprehensive overview how modifications intrinsically affect alterations cell extrinsically responses microenvironment (TME). We review strategies for modulating endogenous immunity discuss challenge reshaping TME. Strategies include: combining specific efficient inhibitors against regulators with checkpoint blockers; generating effective programmable gene-editing system enables manipulation individual sites; establishing enhance T or natural killer cells; using nanoparticles specifically tumor-associated macrophages (TAMs) deliver messenger RNA small interfering A-related molecules repolarize TAMs, enabling them remodel The goal help field understand shape TME so better immunotherapy be designed developed.

Language: Английский

---

METTL3: a multifunctional regulator in diseases

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Language: Английский

---

Hypoxia-Responsive lncRNA AC115619 Encodes a Micropeptide That Suppresses m6A Modifications and Hepatocellular Carcinoma Progression

Cancer Research, Journal Year: 2023, Volume and Issue: 83(15), P. 2496 - 2512

Published: June 16, 2023

Long noncoding RNAs (lncRNA) regulate a number of aspects cancer biology. Recent research has shown that lncRNAs can encode micropeptides mediate their functions in tumors. Here, we revealed the liver-specific putative lncRNA, AC115619, is expressed at low levels hepatocellular carcinoma (HCC) and encodes micropeptide, designated as AC115619-22aa. AC115619 played crucial role regulation tumor progression was prognostic indicator HCC. The encoded micropeptide AC115619-22aa inhibited HCC by binding to WTAP impeding assembly N6-methyladenosine (m6A) methyltransferase complex, which regulates expression tumor-associated genes, such SOCS2 ATG14. cotranscribed with adjacent upstream coding gene APOB, hypoxia induced transcriptional repression both APOB controlling HIF1A/HDAC3 HNF4A signaling. In animal patient-derived models, reduced global m6A suppressed growth. conclusion, this study establishes its potential markers therapeutic targets for patients HCC.A lncRNA impedes formation methylation complex lower reduce growth carcinoma.

Language: Английский

---

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(9), P. 3874 - 3887

Published: Jan. 1, 2022

Although m6A modifications are associated with tumor progression, and anti-tumor immune responses, the role of regulators in HPV-related carcinogenesis has not been well resolved.To provide evidence for identify potential therapeutic targets cancers, integrative analyses 1,485 head neck squamous cell carcinoma (HNSC) patients 507 cervical (CESC) was performed identified that an regulator, METTL3, highly expressed tumors related to poor prognosis HNSC CESC.In HPV-positive tumors, METTL3 positively HPV status, such as integration E6 unspliced-E6 expression, p16 expression.Further analysis demonstrated high status negatively correlated infiltrations facilitated expression immunosuppressive checkpoint molecules (i.e., PD-L1).Cell-derived xenograft models inhibitor combined anti-PD1 therapy promoted immunotherapy CESC vivo.Overall, this study is serves a mediator microenvironment HPV-associated cancer, which provides promising target anti-cancer immunotherapy.

Language: Английский

---

N6‐methyladenosine (m6A) modification in gynecological malignancies

Journal of Cellular Physiology, Journal Year: 2022, Volume and Issue: 237(9), P. 3465 - 3479

Published: July 8, 2022

N6-methyladenosine (m6A) modification is one of the most abundant modifications in eukaryotic mRNA, regulated by m6A methyltransferase and demethylase. modified RNA specifically recognized bound recognition proteins, which mediate splicing, maturation, exonucleation, degradation, translation. In gynecologic malignancies, modification-related molecules are expressed aberrantly, significantly altering posttranscriptional methylation level target genes their stability. The also regulates related metabolic pathways, thereby controlling tumor development. This review analyzes composition mode action proteins biological functions malignant progression provide new ideas for early clinical diagnosis targeted therapy malignancies.

Language: Английский

---

METTL3-induced lncRNA GBAP1 promotes hepatocellular carcinoma progression by activating BMP/SMAD pathway

Biology Direct, Journal Year: 2023, Volume and Issue: 18(1)

Published: Sept. 1, 2023

Hepatocellular carcinoma (HCC) is one of the most common and challenging cancers in world. N6-methyladenosine (m6A) modification long non-coding RNAs (lncRNAs) play critical roles progression HCC. However, there are few reports on genome-wide screening functional annotations m6A-methylated lncRNAs HCC.The expression levels m6A methyltransferase METTL3 association with prognosis HCC were determined by RT-qPCR, public dataset platforms. Then, RNA-seq, Pearson correlation analysis, MeRIP-qPCR, RNA half-life assay, gene site-directed mutation, RIP assay RT-qPCR analysis employed to determine downstream target Subsequently, lncRNA glucosylceramidase beta pseudogene 1 (GBAP1) Kaplan-meier curves, vitro experiments vivo tumorigenesis lung metastasis models. pathway GBAP1 explored GO biological process, KEGG enrichment, luciferase reporter rescue so on.METTL3 was upregulated closely related prognosis. And induced acting as writer IGF2BP2 worked its reader. Clinically, significantly associated tumor size, venous infiltration, TNM stage HCC, Functionally, promoted growth both vivo. Furthermore, acted molecular sponge for miR-22-3p increase bone morphogenetic protein receptor type 1A (BMPR1A), which then activated BMP/SMAD cells.Our findings demonstrated that METTL3-induced migration, invasion proliferation cells via GBAP1/miR-22-3p/BMPR1A/SMAD axis. could be a potential indicator therapeutic

Language: Английский

---

Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(12), P. e007415 - e007415

Published: Dec. 1, 2023

Background Limited response to programmed death ligand-1 (PD-L1)/programmed 1 (PD-1) immunotherapy is a major hindrance of checkpoint in non-small cell lung cancer (NSCLC). The abundance PD-L1 on the tumor surface crucial for responsiveness PD-1/PD-L1 immunotherapy. However, negative control expression and physiological significance inhibition NSCLC remain obscure. Methods Bioinformatics analysis was performed profile investigate long non-coding RNAs that negatively correlated with positively CD8+T infiltration NSCLC. Immunofluorescence, vitro PD-1 binding assay, T cell-induced apoptosis assays vivo syngeneic mouse models were used functional roles LINC02418 mmu-4930573I07Rik regulating anti-PD-L1 therapeutic efficacy molecular mechanism LINC02418-enhanced downregulation explored by immunoprecipitation, RNA immunoprecipitation (RIP), ubiquitination assays. RIP, luciferase reporter, messenger degradation m6A modification or expression. immunohistochemistry (IHC) verification determine LINC02418, infiltration. Results regulator infiltration, predicting favorable clinical outcomes patients downregulates enhancing mediated E3 ligase Trim21. Both hsa-LINC02418 (its homologous mice) regulate via Trim21, inducing . Furthermore, METTL3 N6-methyladenosine (m6A) YTHDF2 reader upregulates mmu-4930573I07Rik. In NSCLC, inversely Conclusion functions as cells promoting through ubiquitin-proteasome pathway. regulated METTL3/YTHDF2-mediated modification. This study illuminates underlying mechanisms regulation presents promising target improving effectiveness therapy

Language: Английский

---

Crosstalk between m6A modification and non-coding RNAs in HCC

Cellular Signalling, Journal Year: 2024, Volume and Issue: 117, P. 111076 - 111076

Published: Feb. 2, 2024

Language: Английский

---

Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3

Bioengineered, Journal Year: 2022, Volume and Issue: 13(2), P. 3108 - 3121

Published: Jan. 17, 2022

Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib a first-line agent approved the treatment of HCC. However, frequent resistance HCC cells to sorafenib greatly reduces its efficacy. Herein, we describe novel long non-coding RNA (lncRNA) conferring resistance. Long intergenic non-protein coding 1273 (LINC01273) was significantly overexpressed human and sorafenib-resistant tissues, linking it poor overall relapse-free survival. We established Huh7 (Huh7-SR) SMMC-7721 (SMMC-7721-SR) cells, found that knockdown LINC01273 repressed viability, colony formation, DNA synthesis rate Huh7-SR SMMC-7721-SR cells. The level N6-methyladenosine (m6A) decreased, which rescued by silencing. Mechanistically, complementarity bound miR-600, served as 'reservoir' increasing miR-600 stability, facilitating targeting methyltransferase 3 (METTL3), m6A 'writer', resulting reducing METTL3 level. In addition, modified m6A, increased modification, followed decay presence YTHDF2, 'reader'. Our findings reveal key role newly identified LINC01273/miR-600/METTL3 feedback regulatory axis may be promising effective intervention

Language: Английский

---

PLAGL2 promotes Snail expression and gastric cancer progression via UCA1/miR-145-5p/YTHDF1 axis

Carcinogenesis, Journal Year: 2023, Volume and Issue: 44(4), P. 328 - 340

Published: March 31, 2023

Although great progress has made in gastric cancer (GC) the past years, overall 5-year survival rate remains to be low for advanced GC patients. A recent study showed that PLAGL2 was increased and enhanced proliferation metastasis of GC. Nevertheless, underlying mechanism still needs investigated.Gene protein expressions were assessed using RT-qPCR western blot. The migration, invasion cells examined scratch assay, CCK-8 assay Transwell respectively. ChIP-PCR, dual-luciferase RIP-qPCR CoiP utilized confirm interaction among PLAGL2, UCA1, miR-145-5p YTHDF1 as well METTL3, eEF-2. mouse xenograft model used further regulatory network.PLAGL2 bound upstream promoter which regulated by sponging miR-145-5p. METTL3 can mediate m6A modification level Snail. recognized m6A-modified Snail interacting with eEF-2 thus promoted expression, eventually induced epithelial-mesenchymal transition (EMT) GC.Overall, our demonstrates enhances expression progression via UCA1/miR-145-5p/YTHDF1 axis, suggesting may become a therapeutic target treatment.

Language: Английский

---