bims-rimeca 2021-10-10 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2021–10–10
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma.
N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells.
Characterization of Modification Patterns, Biological Function, Clinical Implication, and Immune Microenvironment Association of m6A Regulators in Pancreatic Cancer.
N6-Methyladenosine RNA Modification: An Emerging Immunotherapeutic Approach to Turning Up Cold Tumors.
LncRNA HCG11 mediated by METTL14 inhibits the growth of lung adenocarcinoma via IGF2BP2/LATS1.
M6A Classification Combined With Tumor Microenvironment Immune Characteristics Analysis of Bladder Cancer.
m6A Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pancreatic Cancer.
Integrative Analysis Reveals Potentially Functional N6-Methylandenosine-Related Long Noncoding RNAs in Colon Adenocarcinoma.
Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11.

Biochem Biophys Res Commun. 2021 Oct 05. pii: S0006-291X(21)00819-6. [Epub ahead of print]580 48-55

The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma.

Jiang Zou, Xiaowu Zhong, Xi Zhou, Qiyue Xie, Zhao Zhao, Xiaolan Guo, Yixiang Duan.

  Esophageal squamous cell carcinoma (ESCC) is one of the most lethal human cancers with a lower 5-year survival rate. N6-methyladenosine (m6A) methylation, an important epigenetic modification, has been reported to associate with physiological and pathological processes of cancers. However, its role in ESCC remains unclear. In this work, we found that the m6A levels were elevated in ESCC cancer tissues and ESCC cells. The PPI network demonstrated that METTL3, METTL14, WTAP, RBM15, and KIAA1429 were all significantly associated with each other. Moreover, we found a significant upregulation of METTL3 mRNA and protein amounts in ESCC tissues. The METTL3 mRNA expression level of tissues had associations with ESCC differentiation extent and sex (p < 0.05). The METTL3 mRNA expression level of tissues, sensitivity for diagnosing ESCC was 75.00%, specificity was 72.06% and area under the ROC curve was 0.8030. Depletion of METTL3 markedly diminished m6A levels in human ESCC cell lines and METTL3 overexpression restored the reduction in m6A levels. These results suggested that METTL3 is the primary enzyme that modulates m6A methylation and a critical regulatory factor in ESCC. Additionally, METTL3 knockdown significantly suppressed the ESCC cell proliferation, while METTL3 overexpression markedly promoted ESCC cell proliferation both in cell and animal models. These results demonstrated that METTL3 promotes ESCC development. Furthermore, METTL3 may modulate the cell cycle of ESCC cells through a p21-dependent pattern. METTL3-guided m6A modification may contribute to the progression of ESCC via the p21-axis. Our study is the first investigation to report that METTL3-mediated m6A methylation plays a crucial role in ESCC oncogenesis and highlights that METTL3 might be a potential biomarker and therapeutic target for ESCC patients.

Keywords:  Esophageal squamous cell carcinoma; Methyltransferase-like 3; N6-methyladenosine (m6A)

DOI:  https://doi.org/10.1016/j.bbrc.2021.05.048
Redox Biol. 2021 Sep 26. pii: S2213-2317(21)00311-6. [Epub ahead of print]47 102151

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells.

Min Shen, Yujia Li, Yingqian Wang, Jiangjuan Shao, Feng Zhang, Guoping Yin, Anping Chen, Zili Zhang, Shizhong Zheng.

  Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that the total levels of N6-methyladenosine (m6A) modification are evidently increased upon exposure to ferroptosis-inducing compounds due to the upregulation of methylase METTL4 and the downregulation of demethylase FTO. Interestingly, RNA-seq shows that m6A modification appears to trigger autophagy activation by stabilizing BECN1 mRNA, which may be the potential mechanism for m6A modification-enhanced HSC ferroptosis. Importantly, YTHDF1 is identified as a key m6A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent BECN1 plasmid-induced HSC ferroptosis. Noteworthy, YTHDF1 promotes BECN1 mRNA stability and autophagy activation via recognizing the m6A binding site within BECN1 coding regions. In mice, erastin treatment alleviates liver fibrosis by inducing HSC ferroptosis. HSC-specific inhibition of m6A modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis. Moreover, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis and m6A modification in advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving sorafenib monotherapy. Attractively, the m6A modification upregulation, autophagy activation, and ferroptosis induction occur in human HSCs. Overall, these findings reveal novel signaling pathways and molecular mechanisms of ferroptosis, and also identify m6A modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.

Keywords:  Autophagy; Ferroptosis; Hepatic stellate cell; Liver fibrosis; YTHDF1; m6A modification

DOI:  https://doi.org/10.1016/j.redox.2021.102151
Front Genet. 2021 ;12 702072

Characterization of Modification Patterns, Biological Function, Clinical Implication, and Immune Microenvironment Association of m6A Regulators in Pancreatic Cancer.

Kun Fang, Hairong Qu, Jiapei Wang, Desheng Tang, Changsheng Yan, Jiamin Ma, Lei Gao.

  Objective: N6-methyladenosine (m6A) modification may modulate various biological processes. Nonetheless, clinical implications of m6A modification in pancreatic cancer are undefined. Herein, this study comprehensively characterized the m6A modification patterns in pancreatic cancer based on m6A regulators. Methods: Genetic mutation and expression pattern of 21 m6A regulators and their correlations were assessed in pancreatic cancer from TCGA dataset. m6A modification patterns were clustered using unsupervised clustering analysis in TCGA and ICGC datasets. Differences in survival, biological functions and immune cell infiltrations were assessed between modification patterns. A m6A scoring system was developed by principal component analysis. Genetic mutations and TIDE scores were compared between high and low m6A score groups. Results: ZC3H13 (11%), RBM15B (9%), YTHDF1 (8%), and YTHDC1 (6%) frequently occurred mutations among m6A regulators. Also, most of regulators were distinctly dysregulated in pancreatic cancer. There were tight crosslinks between regulators. Two m6A modification patterns were constructed, with distinct prognoses, immune cell infiltration and biological functions. Furthermore, we quantified m6A score in each sample. High m6A scores indicated undesirable clinical outcomes. There were more frequent mutations in high m6A score samples. Lower TIDE score was found in high m6A score group, with AUC = 0.61, indicating that m6A scores might be used for predicting the response to immunotherapy. Conclusion: Collectively, these data demonstrated that m6A modification participates pancreatic cancer progress and ornaments immune microenvironment, providing an insight into pancreatic cancer pathogenesis and facilitating precision medicine development.

Keywords:  N6-methyladenosine regulators; immune microenvironment; immunotherapy; pancreatic cancer; prognosis

DOI:  https://doi.org/10.3389/fgene.2021.702072
Front Cell Dev Biol. 2021 ;9 736298

N6-Methyladenosine RNA Modification: An Emerging Immunotherapeutic Approach to Turning Up Cold Tumors.

Lei Zhan, Junhui Zhang, Suding Zhu, Xiaojing Liu, Jing Zhang, Wenyan Wang, Yijun Fan, Shiying Sun, Bing Wei, Yunxia Cao.

  Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as "cold tumors," have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

Keywords:  N6-methyladenosine RNA modification; biomarker; cold tumors; hot tumors; immunotherapy; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2021.736298
Biochem Biophys Res Commun. 2021 Oct 02. pii: S0006-291X(21)01392-9. [Epub ahead of print]580 74-80

LncRNA HCG11 mediated by METTL14 inhibits the growth of lung adenocarcinoma via IGF2BP2/LATS1.

Jun Mao, Hailong Qiu, Liling Guo.

  Lung adenocarcinoma (LUAD) is a common malignancy the pathogenesis of which is terribly complicated and remains largely unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous RNA molecules that are involved in various malignant processes. In this study, we explored the roles of lncRNA Human leukocyte antigen complex group 11 (HCG11) in LUAD. Our data revealed that lncRNA HCG11 expression was downregulated in LUAD, which was modulated by the hypermethylation of HCG11 promoter and Methyltransferase Like 14 (METTL14) mediated N6-methyladenosine (m6A) modification. The m6A modification of HCG11 promoted its nuclear exportation and binding by Insulin Like Growth Factor 2 MRNA Binding Protein 2 (IGF2BP2), resulting in increased stability. HCG11 could recruit IGF2BP2 to target Large Tumor Suppressor Kinase 1 (LATS1) mRNA to enhance the stability and promote the expression of LATS1. HCG11 served as a tumor suppressor to restrain tumor growth in LUAD by regulating LATS1. In summary, this study demonstrated that HCG11 mediated by METTL14 inhibited the growth of lung adenocarcinoma via IGF2BP2/LATS1.

Keywords:  HCG11; IGF2BP2; LATS1; Long non-coding RNA; Lung adenocarcinoma; METTLE14

DOI:  https://doi.org/10.1016/j.bbrc.2021.09.083
Front Oncol. 2021 ;11 714267

M6A Classification Combined With Tumor Microenvironment Immune Characteristics Analysis of Bladder Cancer.

Huili Zhu, Xiaocan Jia, Yuping Wang, Zhijuan Song, Nana Wang, Yongli Yang, Xuezhong Shi.

   Background: Studies have shown that N6-methyl adenosine (m6A) plays an important role in cancer progression; however, the underlying mechanism of m6A modification in tumor microenvironment (TME) cell infiltration of bladder cancer remains unclear. This study aimed to investigate the role of m6A modification in TME cell infiltration of bladder cancer.
Methods: The RNA expression profile and clinical data of bladder cancer were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. We assessed the m6A modification patterns of 664 bladder cancer samples based on 20 m6A regulators through unsupervised clustering analysis and systematically linked m6A modification patterns to TME cell infiltration characteristics. Gene ontology and gene set variation analyses were conducted to analyze the underlying mechanism based on the assessment of m6A methylation regulators. Principal component analysis was used to construct the m6A score to quantify m6A modification patterns of bladder cancer.
Results: The genetic and expression alterations in m6A regulators were highly heterogeneous between normal and bladder tissues. Three m6A modification patterns were identified. The cell infiltration characteristics were highly consistent with the three immune phenotypes, including immune rejection, immune inflammation, and immune desert. The biological functions of three m6A modification patterns were different. Cox regression analyses revealed that the m6A score was an independent signature with patient prognosis (HR = 1.198, 95% CI: 1.031-1.390). Patients with a low-m6A score were characterized by increased tumor mutation burden, PD-L1 expression, and poorer survival. Patients in the low-m6A score group also showed significant immune responses and clinical benefits in the CTLA-4 immunotherapy cohort (p =0.0069).
Conclusions: The m6A methylation modification was related to the formation of TME heterogeneity and complexity. Assessing the m6A modification pattern of individual bladder cancer will improve the understanding of TME infiltration characteristics.

Keywords:  bladder cancer; immunotherapy; m6A; mutation burden; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.714267
Front Immunol. 2021 ;12 739768

m6A Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pancreatic Cancer.

Mengyu Sun, Meng Xie, Tongyue Zhang, Yijun Wang, Wenjie Huang, Limin Xia.

  Recent studies have shown that RNA N6-methyladenosine (m6A) modification plays an important part in tumorigenesis and immune-related biological processes. However, the comprehensive landscape of immune cell infiltration characteristics in the tumor microenvironment (TME) mediated by m6A methylation modification in pancreatic cancer has not yet been elucidated. Based on consensus clustering algorithm, we identified two m6A modification subtypes and then determined two m6A-related gene subtypes among 434 pancreatic cancer samples. The TME characteristics of the identified gene subtypes were highly consistent with the immune-hot phenotype and the immune-cold phenotype respectively. According to the m6A score extracted from the m6A-related signature genes, patients can be divided into high and low m6A score groups. The low score group displayed a better prognosis and relatively strong immune infiltration. Further analysis showed that low m6A score correlated with lower tumor mutation burden and PD-L1 expression, and indicated a better response to immunotherapy. In general, m6A methylation modification is closely related to the diversity and complexity of immune infiltration in TME. Evaluating the m6A modification pattern and immune infiltration characteristics of individual tumors can help deepen our understanding of the tumor microenvironment landscape and promote a more effective clinical practice of immunotherapy.

Keywords:  immunotherapy; m6A; mutation burden; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.739768
Front Genet. 2021 ;12 739344

Integrative Analysis Reveals Potentially Functional N6-Methylandenosine-Related Long Noncoding RNAs in Colon Adenocarcinoma.

Xinjie Tan, Qian Li, Qinya Zhang, Gang Fan, Zhuo Liu, Kunyan Zhou.

  N6-methyladenosine (m6A) is one of the most prevalent RNA modifications in mRNA and non-coding RNA. In this study, we identified 10 upregulated m6A regulators at both mRNA and protein levels, and 2,479 m6A-related lncRNAs. Moreover, the m6A-related long noncoding RNAs (lncRNAs) could clearly stratify the colon adenocarcinoma (COAD) samples into three subtypes. The subtype 2 had nearly 40% of samples with microsatellite instability (MSI), significantly higher than the two other subtypes. In accordance with this finding, the inflammatory response-related pathways were highly activated in this subtype. The subtype-3 had a shorter overall survival and a higher proportion of patients with advanced stage than subtypes 1 and 2 (p-value < 0.05). Pathway analysis suggested that the energy metabolism-related pathways might be aberrantly activated in subtype 3. In addition, we observed that most of the m6A readers and m6A-related lncRNAs were upregulated in subtype 3, suggesting that the m6A readers and the m6A-related lncRNAs might be associated with metabolic reprogramming and unfavorable outcome in COAD. Among the m6A-related lncRNAs in subtype 3, four were predicted as prognostically relevant. Functional inference suggested that CTD-3184A7.4, RP11-458F8.4, and RP11-108L7.15 were positively correlated with the energy metabolism-related pathways, further suggesting that these lncRNAs might be involved in energy metabolism-related pathways. In summary, we conducted a systematic data analysis to identify the key m6A regulators and m6A-related lncRNAs, and evaluated their clinical and functional importance in COAD, which may provide important evidences for further m6A-related researches.

Keywords:  N6-methylAdenosine (m6A); colon adenocarcinoma; long noncoding RNAs; m6A-related lncRNAs; metabolic reprogramming

DOI:  https://doi.org/10.3389/fgene.2021.739344
J Cell Mol Med. 2021 Oct 05.

Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11.

Zhuoyang Fan, Guowei Yang, Wei Zhang, Qian Liu, Guangqin Liu, Pingping Liu, Ligang Xu, Jianhua Wang, Zhiping Yan, Hong Han, Rong Liu, Minfeng Shu.

  Residue hepatocellular carcinoma (HCC) cells enduring hypoxic environment triggered by interventional embolization obtain more malignant potential with little clarified mechanism. The N6 -methyladenosine (m6 A) biological activity plays essential roles in diverse physiological processes. However, its role under hypoxic condition remains largely unexplored. RT-qPCR and Western blot were used to evaluate METTL14 expression in hypoxic HCC cells. MDA assay and electronic microscopy photography were used to evaluate ferroptosis. The correlation between SLC7A11 and METTL14 was conducted by bioinformatical analysis. Flow cytometry was used to verify the effect of SLC7A11 on ROS production. Cell counting kit-8 assay was performed to detect cells proliferation ability. Hypoxia triggered suppression of METTL14 in a HIF-1α-dependent manner potently abrogated ferroptosis of HCC cells. Mechanistic investigation identified SLC7A11 was a direct target of METTL14. Both in vitro and in vivo assay demonstrated that METTL14 induced m6 A modification at 5'UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2-dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14-induced tumour-suppressive effect in hypoxic HCC. Our investigations lay the emphasis on the hypoxia-regulated ferroptosis in HCC cells and identify the HIF-1α /METTL14/YTHDF2/SLC7A11 axis as a potential therapeutic target for the HCC interventional embolization treatment.

Keywords:  METTL14; SLC7A11; ferroptosis; hepatocellular carcinoma; hypoxia

DOI:  https://doi.org/10.1111/jcmm.16957