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N1-methyladenosine (m1A) modification widely participates in the occurrence and progression of numerous diseases. Nevertheless, the potential roles of m1A in the tumor immune microenvironment (TIME) are still not fully understood. Based on 10 m1A methylation regulators, we comprehensively explored the m1A modification patterns in 502 patients with oral squamous cell carcinoma (OSCC). The m1A modification patterns were correlated with TIME characteristics and the m1A score was established to evaluate the effect of the m1A modification patterns on individual OSCC patients. The TIME characteristics and survival outcomes under the three m1A modification patterns were significantly distinct. OSCC patients in the high m1A score group were characterized by poorer prognosis, lower immune infiltration, lower ssGSEA score, lower expression levels of immune checkpoint molecules, and higher tumor mutation loads. The present study revealed that m1A modification might be associated with the TIME in OSCC, and has potential predictive ability for the prognosis of OSCC.

Background N1‐methyladenosine (m1A) is a recently identified mRNA modification. However, it is still unclear that how m1A alteration affects the development of colorectal cancer (CRC). Aims The landscape of m1A modification patterns regarding tumor immune microenvironment (TIME) in CRC is a lack of knowledge. Thus, this study will utilize the public database to comprehensively evaluate of multiple m1A methylation regulators in CRC. Methods and results We retrospectively analyzed 398 patients with CRC and 39 healthy people for negative control, using the The Cancer Genome Atlas (TCGA) database to evaluate m1A modification patterns regarding tumor immune microenvironment (TIME) in CRC. The m1Ascore was developed via principal component analysis. And its clinical value in prognosis of CRC was further explored. Our study revealed 12 key m1A‐related DEGs including CLDN3, MUC2 and CCDC85B which are identified associated with invasion and metastasis in CRC. The most important biological processes linked to weak immune response and poor prognosis were the regulation of RNA metabolism and RNA biosynthesis. Furthermore, we found that compared to patients with low m1A scores, those with high m1A scores had higher percentage, larger tumor burdens, and worse prognosis. Conclusion Significantly diverse m1A modification patterns can be seen in CRC. Through its impact on TIME and immunological dysfunction, the heterogeneity of m1A alteration patterns influences the prognosis of CRC. This study provided novel insights into the m1A modification in CRC which might promote the development of personalized immunotherapy strategies.

Cerebral ischaemia‒reperfusion injury (IRI), during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m 1 A) is an RNA modification that can affect gene expression and RNA stability. The m 1 A landscape and potential functions of m 1 A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m 1 A modification in normal and OGD/R-treated mouse neurons and the effect of m 1 A on diverse RNAs. We investigated the m 1 A landscape in primary neurons, identified m 1 A-modified RNAs, and found that OGD/R increased the number of m 1 A RNAs. m 1 A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA–RNA binding proteins (RBPs) interactions and circRNA translation. We showed that m 1 A modification mediates the circRNA/lncRNA‒miRNA–mRNA competing endogenous RNA (ceRNA) mechanism and that 3' untranslated region (3’UTR) modification of mRNAs can hinder miRNA–mRNA binding. Three modification patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m 1 A-regulatory specificity. Systematic analysis of the m 1 A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA modification and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

recently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration. Based on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples. We finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient's m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis. This research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1A RNA modification plays critical role in many biological processes. However, the role of m1A modification in CRC remains unclear. Here, we find that the m1A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6‐adenosine‐methyltransferase complex catalytic subunit (METTL3) expression, probably due to m1A modification of METTL3 mRNA, followed by m6A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3. Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. Here, we identified the important role of ALKBH1‐catalyzed m1A modification in CRC metastasis. ALKBH1‐mediated m1A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Neuroblastoma tightly linked with genetic abnormality. The core genes responsible for RNA N 1 -methyladenosine (m 1 A) modification are critical in tumor development. Nevertheless, few reports revealed the function of m 1 A modification core gene polymorphisms and the neuroblastoma risk. We carried out this study to verify the association of 12 single-nucleotide polymorphisms (SNPs) with neuroblastoma susceptibility. This study recruited 898 cases with newly diagnosed neuroblastoma and 1734 Healthy controls from eight medical centers. We selected 12 SNPs from m 1 A modification genes ALKBH1 , TRMT6 , TRMT61B , and TRMT10C , and genotypes were determined by the TaqMan method. We used univariable and multivariable logistic regression models to analyze the association of SNPs with neuroblastoma risk, followed by stratified analysis. Statistical analysis showed that TRMT6 rs236170 GG (AOR = 1.23, 95% CI = 1.02–1.50, P  = 0.034), rs451571 CC (AOR = 1.46, 95% CI = 1.01–2.11, P  = 0.043), rs236188 AA (AOR = 2.65, 95% CI = 1.16–6.07, P  = 0.021), rs236110 AA (AOR = 1.91, 95% CI = 1.29–2.82, P  = 0.001), and ALKBH1 rs6494 AA (AOR = 4.27, 95% CI = 1.31–13.93, P  = 0.016), rs176942 GG (AOR = 1.98, 95% CI = 1.35–2.89, P  = 0.0005) were neuroblastoma risk variants; the ALKBH1 rs1048147 CC (AOR = 0.80, 95% CI = 0.68–0.94, P  = 0.007) was inverse associated with neuroblastoma risk. The eQTL analysis showed that functional annotation of rs6494 T > A may be potential function variants through decreasing ALKBH1 gene expression mRNA, rs451571 T > C, rs236188 G > A, rs236110 C > A are associated with neuroblastoma risk through increasing the expression of its nearby genes RP5-967N21.11 and lowering the expression of MCM8 . Our research showed some SNPs in the m 1 A modification core genes are related to neuroblastoma. Clinical perspectives (i) Few reports have revealed the function of m 1 A modification core gene polymorphisms in neuroblastoma risk. (ii) After genotyping 12 SNPs with potential functions in four m 1 A modification core genes in children with neuroblastoma and healthy controls, we found several neuroblastoma predisposition loci, including TRMT6 rs236170, rs451571, rs236188, rs236110, and ALKBH1 rs6494, rs176942, and rs1048147. The eQTL assessment demonstrated that rs6494 T > A may be a potential functional variant by decreasing ALKBH1 mRNA expression. (iii) Our research is the first to reveal m 1 A modification core gene SNPs and neuroblastoma risk. Graphical Abstract

RNA methylation plays crucial roles in gene expression and has been indicated to be involved in tumorigenesis, while it is still unclear whether m1A modifications have potential roles in the prognosis of hepatocellular carcinoma (HCC). In this study, we comprehensively analyzed RNA sequencing (RNA-seq) data and clinical information using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We collected 10 m1A regulators and performed consensus clustering to determine m1A modification patterns in HCC. The CIBERSORT method was utilized to evaluate the level of immune cell infiltration. Principal component analysis was used to construct the m1A-score model. In the TCGA-LIHC cohort, the expression of all 10 m1A regulators was higher in tumor tissues than in normal control tissues, and 8 of 10 genes were closely related to the prognosis of HCC patients. Two distinct m1A methylation modification patterns (Clusters C1 and C2) were identified by the 10 regulators and were associated with different overall survival, TNM stage and tumor microenvironment (TME) characteristics. Based on the differentially expressed genes (DEGs) between C1 and C2, we identified three gene clusters (Clusters A, B and C). C1 with a better prognosis was mainly distributed in Cluster C, while Cluster A contained the fewest samples of C1. An m1A-score model was constructed using five m1A regulators related to prognosis. Patients with higher m1A scores showed a poorer prognosis than those with lower scores in the TCGA-LIHC and GSE14520 datasets. In conclusions, our study showed the vital role of m1A modification in the TME and progression of HCC. Quantitative evaluation of the m1A modification patterns of individual patients facilitates the development of more effective biomarkers for predicting the prognosis of patients with HCC.

Hepatoblastoma, the most frequently diagnosed primary paediatric liver tumour, bears the lowest somatic mutation burden among paediatric neoplasms. Therefore, it is essential to identify pathogenic germline genetic variants, especially those in oncogenic genes, for this disease. The tRNA methyltransferase 6 noncatalytic subunit (TRMT6) forms a tRNA methyltransferase complex with TRMT61A to catalyse adenosine methylation at position N1 of RNAs. TRMT6 has displayed tumour‐promoting functions in several cancer types. However, the contribution of its genetic variants to hepatoblastoma remains unclear. In this study, we investigated the association between four TRMT6 polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A and rs236110 C > A) and the risk of hepatoblastoma in a cohort of 313 cases and 1446 healthy controls. Germline DNA was subjected to polymorphism genotyping via the TaqMan qPCR method. Odds ratio (OR) and 95% confidence interval (CI) were used to determine hepatoblastoma susceptibility variants. The rs236170 A > G, rs236188 G > A and rs236110 C > A polymorphisms were significantly associated with hepatoblastoma risk. Combination analysis of the four polymorphisms revealed that children bearing 1–4 risk genotypes were at significantly enhanced hepatoblastoma risk compared to those without risk genotype (adjusted OR = 1.52, 95% CI = 1.19–1.95, p = 0.0008). We also conducted stratification analyses by age, sex and clinical stage. Ultimately, we found that the rs236110 C > A was significantly associated with the downregulation of MCM8, a neighbouring gene of TRMT6. In conclusion, we identified three susceptibility loci in the TRMT6 gene for hepatoblastoma. Our findings warrant further validation by extensive case–control studies across different ethnicities.

Coronary microembolization (CME) refers to embolism in the coronary microcirculation. This study showed a reduction in succinyl transferase (CPT1A) and the succinylation substrate (succinyl-CoA) in cardiomyocytes in CME models, suppressing the succinylation of the mitochondrially localized protein TRMT10C. Suppression of succinylation promotes KPNA4 recognition of two nuclear localization signals (NLSs), KAKR and KKK(X) KVKK, in TRMT10C, which induces the transport of TRMT10C from the cytoplasm to the nucleus rather than to the mitochondria. Nuclear TRMT10C induces YTHDF2-mediated decay of TAFAZZIN and NLRX1 through m1A modifications. The reduction in TAFAZZIN and NLRX1 is associated with multiple detrimental effects, such as inflammation mediated by NF-κB and NLRP3, reactive oxygen species (ROS) production, and suppression of mitophagy. TRMT10C knockdown suppressed the accumulation of TRMT10C in the nucleus. It restored NLRX1 and TAFAZZIN protein levels in cardiomyocytes under hypoxia. However, the deficiency of TRMT10C in the mitochondria did not improve-or even worsened-with TRMT10C knockdown. Inducing TRMT10C succinylation via CPT1A overexpression led to the redistribution of TRMT10C to the mitochondria rather than the nucleus, which is likely a better approach for improving cardiomyocyte function under hypoxia than direct TRMT10C knockdown. This study reveals a novel pathological mechanism underlying CME and suggests potential therapeutic targets for this disease.

N1-methyladenosine (m1A) modification is an epigenetic change that occurs on RNA molecules, regulated by a suite of enzymes including methyltransferases (writers), demethylases (erasers), and m1A-recognizing proteins (readers). This modification significantly impacts the function of RNA and various biological processes by affecting the structure, stability, translation, metabolism, and gene expression of RNA. Thereby, m1A modification is closely associated with the occurrence and progression of cancer. This review aims to explore the role of m1A modification in tumor immunity. m1A affects tumor immune responses by directly regulating immune cells and indirectly modulating tumor microenvironment. Besides, we also discuss the implications of m1A-mediated metabolic reprogramming and its nexus with immune checkpoint inhibitors, unveiling promising avenues for immunotherapeutic intervention. Additionally, the m1AScore, established based on the expression patterns of m1A modification, can be used to predict tumor prognosis and guide personalized therapy. Our review underscores the significance of m1A modification as a burgeoning frontier in cancer biology and immuno-oncology, with the potential to revolutionize cancer treatment strategies.