bims-rimeca 2023-07-16 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023–07–16
ten papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Downregulated FTO promotes microRNA-155-mediated inflammatory response in cerebral ischemia/reperfusion injury.
METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP.
Dysregulated m6A methylation modification is associated with human peri-implantitis - A pilot study.
Identification and validation of m6A-GPI signatures as a novel prognostic model for colorectal cancer.
Global distribution, toxicity to humans and animals, biodegradation, and nutritional mitigation of deoxynivalenol: A review.
RNA m6A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO.
Role of N6-methyladenosine RNA modification in gastric cancer.
ALKBH5-mediated m6A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability.
A risk model constructed using 14 N6-methyladenosine-related lncRNAs as a new prognostic marker that correlates with the immunomodulatory effect and drug sensitivity in colorectal cancer.
Target genes of N6-methyladenosine regulatory protein ALKBH5 are associated with prognosis of patients with lung adenocarcinoma.

Neuroscience. 2023 Jul 10. pii: S0306-4522(23)00307-X. [Epub ahead of print]

Downregulated FTO promotes microRNA-155-mediated inflammatory response in cerebral ischemia/reperfusion injury.

Zheyu Jiang, Linghua Shi, Hao Huang, Dongniang Lei, Linyan Lou, Yijun Jin, Jun Sun, Lizhou Wang.

  This study aimed to elucidate the mechanism for alteration of m6A RNA modification in cerebral ischemia/reperfusion(I/R) injury and identify novel therapeutic targets. A rat cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO) followed by reperfusion. Changes in m6A RNA modification were evaluated by colorimetric quantification. The expression of the m6A methyltransferases METTL3, METTL14, and WTAP, and the demethylases FTO and ALKBH5 were determined using qPCR and western blot analyses.FTO was overexpressed in brain tissues via intracerebroventricular injection of adenoviruses encoding FTO. The protective effect of FTO on m6A RNA modification and cerebral I/R injury was assessed.MeRIP assays were used to detect the impact of FTO overexpression on m6A modification of pri-miR-155; qPCR analysis was used to identify its maturation. Finally, the role of miR-155 overexpression in the protective effects of FTO on cerebral I/R injury was examined. m6A levels of total RNA were increased, and m6A methyltransferase FTO expression was decreased in post-I/R injury cerebral tissues. FTO overexpression reversed the increase in m6A RNA modification and attenuated cerebral I/R injury. Furthermore, FTO overexpression increased the m6A modification of pri-miR-155 and enhanced its maturation to form miR-155. Notably, miR-155 overexpression blunted FTO's protective effect against cerebral I/R injury. We propose that downregulation of FTO expression contributes to increased m6A RNA modification in cerebral I/R injury.FTO overexpression reverses increased total m6A RNA modification and exerts a protective effect against cerebral I/R injury via downregulating m6A modification of pri-miR-155 to inhibit its maturation process.

Keywords:  FTO; cerebral ischemia/reperfusion injury; m(6)A; miR-155

DOI:  https://doi.org/10.1016/j.neuroscience.2023.07.012
Environ Toxicol. 2023 Jul 14.

METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP.

Guoqiang Li, Junwen Liu, Yinhuai Wang, Hanqi Liu, Jianhan Fu, Yuanqiao Zhao, Yanqing Huang.

   OBJECTIVE: Prostate cancer (PCa) severely affects men's health worldwide. The mechanism of methyltransferase-like 3 (METTL3) in affecting PCa development by regulating miR-148a-3p expression via N6-methyladenosine (m6A) modification was investigated.
METHODS: METTL3, miR-148a-3p, and thioredoxin interacting protein (TXNIP) levels were determined using RT-qPCR and Western blotting. The m6A modification level of miR-148a-3p was observed by Me-RIP assay. Bioinformatics website predicted miR-148a-3p and TXNIP levels in PCa and their correlation, and the binding site between them was verified by dual-luciferase assay. The proliferation, migration, invasion, and apoptosis of PCa cells were examined by CCK-8 assay, Transwell assay, and flow cytometry. A transplanted tumor model was established in nude mice to observe the tumor growth ability, followed by determination of TXNIP levels in tumor tissues by immunohistochemistry.
RESULTS: METTL3 interference restrained the proliferation, migration, and invasion and promoted apoptosis of PCa cells. METTL3 up-regulated miR-148a-3p by promoting the m6A modification of pri-miR-148a-3p in PCa cells. miR-148a-3p overexpression nullified the inhibitory actions of silencing METTL3 on PCa cell growth. miR-148a-3p facilitated PCa cell growth by silencing TXNIP. METTL3 interference inhibited tumor growth by down-regulating miR-148a-3p and up-regulating TXNIP.
CONCLUSION: METTL3 promoted miR-148a-3p by mediating the m6A modification of pri-miR-148a-3p, thereby targeting TXNIP, interfering with METTL3 to inhibit the proliferation, migration and invasion of PCa cells, promote apoptosis, and inhibit tumor growth in nude mice.

Keywords:  METTL3; TXNIP; epigenetics; m6A; miR-148a-3p; pri-miR-148a-3p; prostate cancer

DOI:  https://doi.org/10.1002/tox.23874
J Stomatol Oral Maxillofac Surg. 2023 Jul 10. pii: S2468-7855(23)00171-4. [Epub ahead of print] 101550

Dysregulated m6A methylation modification is associated with human peri-implantitis - A pilot study.

Harini Sri Krishnamoorthy, Balachander Kannan, Dhanraj Ganapathy, Vijayashree Priyadharsini Jayaseelan, Paramasivam Arumugam.

   BACKGROUND: N6-methyladenosine (m6A) RNA modification and its regulatory enzymes play important roles in the modulation of inflammation by regulating inflammation-related gene expression. Dysregulation of m6A has been associated with inflammatory diseases, including periodontitis. This study aimed to investigate the potential role of m6A modification and its master regulatory enzyme METTL3 in patients with peri-implantitis.
MATERIALS AND METHODS: Peri-implant soft tissues from 20 subjects (10 healthy controls and 10 patients with peri-implantitis) were enrolled in this study. Quantitative reverse transcription PCR (RT-qPCR) was used to detect METTL3 gene expression and western blotting was used to detect METTL3 protein expression. The m6A mRNA levels were measured using an m6A-RNA methylation quantification kit. Protein-protein interaction networks and in silico functional analyses were conducted using various bioinformatics tools.
RESULTS: m6A mRNA levels significantly increased in the peri-implantitis group. Higher METTL3 mRNA and protein levels were observed in the peri-implantitis group. High METTL3 expression might influence elevated levels of m6A RNA methylation. In addition, in silico functional analysis indicated that the METTL3 gene and protein were associated with inflammatory pathways.
CONCLUSIONS: Our data provide evidence, for the first time, that dysregulation of m6A modification is associated with peri-implantitis and may represent a strong risk factor for this inflammatory disease.

Keywords:  Genetics; Health; METTL3; Peri-Implantitis; m6A

DOI:  https://doi.org/10.1016/j.jormas.2023.101550
Front Oncol. 2023 ;13 1145753

Identification and validation of m6A-GPI signatures as a novel prognostic model for colorectal cancer.

Bin Ma, Simeng Bao, Yongmin Li.

  In order to develop an N6-methyladenosine-related gene prognostic index (m6A-GPI) that can predict the prognosis in colorectal cancer (CRC), we obtained m6A-related differentially expressed genes (DEGs) based on The Cancer Genome Atlas (TCGA) and m6Avar database, seven genes were screened by weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis. Then, m6A-GPI was constructed based on the risk score. Survival analysis indicated that patients in the lower m6A-GPI group have more prolonged disease-free survival (DFS), and different clinical characteristic groups (tumor site and stage) also showed differential risk scores. In the analysis of the molecular characteristics, the risk score is positively associated with homologous recombination defects (HRD), copy number alterations (CNA), and the mRNA expression-based stemness index (mRNAsi). In addition, m6A-GPI also plays an essential role in tumor immune cell infiltration. The immune cell infiltration in the low m6A-GPI group is significantly higher in CRC. Moreover, we found that CIITA, one of the genes in m6A-GPI was up-regulated in CRC tissues based on real-time RT-PCR and Western blot. m6A-GPI is a promising prognostic biomarker that can be used to distinguish the prognosis of CRC patients in CRC.

Keywords:  CIITA; N6-methyladenosine; colorectal cancer; immune infiltration; prognostic signature

DOI:  https://doi.org/10.3389/fonc.2023.1145753
Compr Rev Food Sci Food Saf. 2023 Jul 08.

Global distribution, toxicity to humans and animals, biodegradation, and nutritional mitigation of deoxynivalenol: A review.

Yuang Tu, Shiqi Liu, Peiran Cai, Tizhong Shan.

  Deoxynivalenol (DON) is one of the main types of B trichothecenes, and it causes health-related issues in humans and animals and imposes considerable challenges to food and feed safety globally each year. This review investigates the global hazards of DON, describes the occurrence of DON in food and feed in different countries, and systematically uncovers the mechanisms of the various toxic effects of DON. For DON pollution, many treatments have been reported on the degradation of DON, and each of the treatments has different degradation efficacies and degrades DON by a distinct mechanism. These treatments include physical, chemical, and biological methods and mitigation strategies. Biodegradation methods include microorganisms, enzymes, and biological antifungal agents, which are of great research significance in food processing because of their high efficiency, low environmental hazards, and drug resistance. And we also reviewed the mechanisms of biodegradation methods of DON, the adsorption and antagonism effects of microorganisms, and the different chemical transformation mechanisms of enzymes. Moreover, nutritional mitigation including common nutrients (amino acids, fatty acids, vitamins, and microelements) and plant extracts was discussed in this review, and the mitigation mechanism of DON toxicity was elaborated from the biochemical point of view. These findings help explore various approaches to achieve the best efficiency and applicability, overcome DON pollution worldwide, ensure the sustainability and safety of food processing, and explore potential therapeutic options with the ability to reduce the deleterious effects of DON in humans and animals.

Keywords:  adsorption; biodegradation; deoxynivalenol; food safety; global occurrence; nutritional mitigation; toxicity

DOI:  https://doi.org/10.1111/1541-4337.13203
JACC Basic Transl Sci. 2023 Jun;8(6): 677-698

RNA m6A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO.

Pujiao Yu, Jiaqi Wang, Gui-E Xu, Xuan Zhao, Xinxin Cui, Jingyi Feng, Jiangpeng Sun, Tianhui Wang, Michail Spanos, Helge Immo Lehmann, Guoping Li, Jiahong Xu, Lijun Wang, Junjie Xiao.

  Cardiac death is a major burden for cancer survivors, yet there is currently no effective treatment for doxorubicin (DOX)-induced cardiotoxicity. Here, we report that circ-ZNF609 knockdown knockdown had cardioprotective effects against DOX-induced cardiomyocyte toxicity. Mechanistically, circ-ZNF609 knockdown alleviated DOX-induced cardiotoxicity through attenuating cardiomyocyte apoptosis, reducing reactive oxygen species production, ameliorating mitochondrial nonheme iron overload. circ-ZNF609 inhibition blocked the elevation of RNA N6-methyladenosine (RNA m6A) methylation level in DOX-treated mice hearts, whereas m6A demethylase fat mass and obesity associated (FTO) acted as the downstream factor of circ-ZNF609. Moreover, the stability of circ-ZNF609 was regulated by RNA m6A methylation alteration, and suppression of RNA m6A methylation by methyltransferase like 14 (METTL14) modulated the function of circ-ZNF609. These data suggest that circ-ZNF609 inhibition represents a potential therapy for DOX-induced cardiotoxicity.

Keywords:  RNA N6-methyladenosine; cardiotoxicity; circ-ZNF609; circular RNA; doxorubicin-induced

DOI:  https://doi.org/10.1016/j.jacbts.2022.12.005
Cell Death Discov. 2023 Jul 13. 9(1): 241

Role of N6-methyladenosine RNA modification in gastric cancer.

Si-Qi Ding, Xue-Ping Zhang, Jun-Peng Pei, Xiao Bai, Jin-Jie Ma, Chun-Dong Zhang, Dong-Qiu Dai.

N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification of mammalian messenger RNA. The m6A modification affects multiple aspects of RNA metabolism, including processing, splicing, export, stability, and translation through the reversible regulation of methyltransferases (Writers), demethylases (Erasers), and recognition binding proteins (Readers). Accumulating evidence indicates that altered m6A levels are associated with a variety of human cancers. Recently, dysregulation of m6A methylation was shown to be involved in the occurrence and development of gastric cancer (GC) through various pathways. Thus, elucidating the relationship between m6A and the pathogenesis of GC has important clinical implications for the diagnosis, treatment, and prognosis of GC patients. In this review, we evaluate the potential role and clinical significance of m6A-related proteins which function in GC in an m6A-dependent manner. We discuss current issues regarding m6A-targeted inhibition of GC, explore new methods for GC diagnosis and prognosis, consider new targets for GC treatment, and provide a reasonable outlook for the future of GC research.

DOI: https://doi.org/10.1038/s41420-023-01485-z
Inflamm Regen. 2023 Jul 14. 43(1): 36

ALKBH5-mediated m6A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability.

Xin Huang, Yixuan Zhao, Daiming Liu, Shuchen Gu, Yunhan Liu, Yimin Khoong, Shenying Luo, Zewei Zhang, Wenzheng Xia, Meng Wang, Hsin Liang, Minxiong Li, Qingfeng Li, Tao Zan.

   BACKGROUND: Impaired wound re-epithelialization contributes to cutaneous barrier reconstruction dysfunction. Recently, N6-methyladenosine (m6A) RNA modification has been shown to participate in the determination of RNA fate, and its aberration triggers the pathogenesis of numerous diseases. Howbeit, the function of m6A in wound re-epithelialization remains enigmatic.
METHODS: Alkbh5‒/‒ mouse was constructed to study the rate of wound re-epithelialization after ALKBH5 ablation. Integrated high-throughput analysis combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq was used to identify the downstream target of ALKBH5. In vitro and in vivo rescue experiments were conducted to verify the role of the downstream target on the functional phenotype of ALKBH5-deficient cells or animals. Furthermore, the interacting reader protein and regulatory mechanisms were determined through RIP-qPCR, RNA pull-down, and RNA stability assays.
RESULTS: ALKBH5 was specifically upregulated in the wound edge epidermis. Ablation of ALKBH5 suppressed keratinocyte migration and resulted in delayed wound re-epithelialization in Alkbh5‒/‒ mouse. Integrated high-throughput analysis revealed that PELI2, an E3 ubiquitin protein ligase, serves as the downstream target of ALKBH5. Concordantly, exogenous PELI2 supplementation partially rescued keratinocyte migration and accelerated re-epithelialization in ALKBH5-deficient cells, both in vitro and in vivo. In terms of its mechanism, ALKBH5 promoted PELI2 expression by removing the m6A modification from PELI2 mRNA and enhancing its stability in a YTHDF2-dependent manner.
CONCLUSIONS: This study identifies ALKBH5 as an endogenous accelerator of wound re-epithelialization, thereby benefiting the development of a reprogrammed m6A targeted therapy for refractory wounds.

Keywords:  ALKBH5; N 6-Methyladenosine (m6a) RNA modification; PELI2; RNA stability; Re-epithelialization

DOI:  https://doi.org/10.1186/s41232-023-00288-0
J Gastrointest Oncol. 2023 Jun 30. 14(3): 1360-1377

A risk model constructed using 14 N6-methyladenosine-related lncRNAs as a new prognostic marker that correlates with the immunomodulatory effect and drug sensitivity in colorectal cancer.

Yajun Huai, Liting Lai, Yuanhui Ren, Bowen Yang, Shasha Yu, Shanshan Wang, Jinhong Mei.

   Background: Colorectal cancer (CRC) remains the most common gastrointestinal malignancy. Despite multimodal therapy, its mortality is high due to recurrence and metastasis. This study developed and verified a risk model consisting of 14 N6-methyladenosine (m6A) long noncoding RNAs (lncRNAs) to assess the prognosis of patients with CRC and investigated its relevance to immune regulation and drug sensitivity.
Methods: The gene expression profiles and clinical data of 446 patients with CRC were retrieved from The Cancer Genome Atlas (TCGA). 14 lncRNAs were screened using the Gene Co-expression Network (corFilter =0.5, P<0.001), and univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct the optimal risk model. The predictive performance and clinical applicability of the model were next verified. In addition, we performed Gene Ontology (GO) enrichment analysis to identify potential biological functions and detected the difference in tumor mutational burden (TMB), immune function, and sensitivity to immunotherapy and other drugs between the high- and low-risk groups to evaluate the application of the constructed risk model in depth.
Results: The model was found to be an appropriate marker for predicting the prognosis of patients with CRC, independent of other clinical features, and demonstrated good precision and broad clinical applicability. It correlated with pathways in the development of cancer and immune-related functions, and patients in the high-risk group had higher tumor immune dysfunction and escape (TIDE) scores. Furthermore, we found significant differences in the overall survival (OS) between patients in the high- and low-tumor mutation burden (TMB) groups, which may work in conjunction with the constructed model to better predict patients' prognosis. Finally, we identified 12 drugs, including A-443654 and sorafenib, with lower half maximal inhibitory concentration (IC50) values in the high-risk group. Conversely, 21 drugs, including gemcitabine and rapamycin, had lower IC50 values in the low-risk group.
Conclusions: We constructed a risk model based on 14 m6A-related lncRNAs that could predict the prognosis of patients with CRC and provided additional therapeutic ideas for their treatment. These findings may additionally serve as a foundation for further studies on regulating CRC via m6A-related lncRNAs.

Keywords:  N6-methyladenosine (m6A); colorectal cancer (CRC); long noncoding RNA (lncRNA); prognostic; risk model

DOI:  https://doi.org/10.21037/jgo-23-412
J Thorac Dis. 2023 Jun 30. 15(6): 3228-3236

Target genes of N6-methyladenosine regulatory protein ALKBH5 are associated with prognosis of patients with lung adenocarcinoma.

Long Jiang, Lan Lan, Yuan Qiu, Weixiang Lu, Wenjun Wang, Ying Huang.

   Background: Lung adenocarcinoma (LUAD) exhibits high fatality rates, and effective treatments are lacking. The expression of the N6-methyladenosine (m6A) regulatory protein ALKBH5 is associated with lung cancer. To identify new therapeutic targets for LUAD, we screened target genes of ALKBH5 and analyzed their potential mechanisms of action.
Methods: LUAD samples from The Cancer Genome Atlas (TCGA) were used to analyze the expression of ALKBH5 and screen for genes with correlated expression. Intersection of the genes upregulated in cells with ALKBH5 silencing with the genes significantly associated with ALKBH5 were defined as ALKBH5 target genes. STRING was used to evaluate interactions between the target genes, and the relationship between ALKBH5 target gene expression and LUAD patient prognosis was analyzed using the R package Survminer. Target genes were evaluated by functional enrichment analyses.
Results: ALKBH5 was highly expressed in LUAD tissues and was significantly associated with a poor prognosis. Fifteen ALKBH5 target genes were identified, primarily enriched in protein processing in the endoplasmic reticulum, transcriptional coregulator activity, and cell activation involved in the immune response. Upregulation of ZNF777, TCOF1, CPLX2, and ABL1 was associated with a poor prognosis, whereas upregulation of ZER1, VPS53, and RRBP1 was associated with a good prognosis.
Conclusions: This study provides potential therapeutic targets for LUAD and a basis for further studies on the mechanism underlying the effects of ALKBH5.

Keywords:  ALKBH5; Lung adenocarcinoma (LUAD); N6-methyladenosine (m6A); enrichment analysis; prognosis

DOI:  https://doi.org/10.21037/jtd-22-1464