Genetics and Epigenetics of RNA Methylation System in Human Cancers

Editors

Shicheng Guo

Arrowhead Pharmaceuticals

Shenying Fang

Southern University of Science and Technology

Dingyuan Luo

Department of Thyroid Surgery, Sun Yat-sen Memorial Hospital

Xiang Shu

Memorial Sloan Kettering Cancer Center

Zhifu Sun

Mayo Clinic

Xiangqian Zheng

Tianjin Medical University Cancer Institute and Hospital

Impact

Original Research

01 June 2021

Correlation Analysis Between MTHFR C677T Polymorphism and Uterine Fibroids: A Retrospective Cohort Study

Jiahui Shen

, 7 more and

Qiwen Yuan

4,195 views

2 citations

The presumptive outline of m5C RNA modification in HNSCC. Methyltransferases of the NSUN family and DNMT family are the main m5C “writers.” Among them, NSUN5 is predicted to methylate KRT83, KRT79, and BPIFA1; whereas DNMT1 and DNMT3A target PRR27, NPS, and STATH. TET2 and TET3 serve as m5C “erasers,” which regulate RNA m5C dynamics together with “writers” in the nucleus. m5C readers bind m5C-modified RNA and modulate the processes of mRNA translation, alternative splicing, and RNA decay. Specifically, ALYREF functions in the nucleus and regulates mRNA export, while YBX1 maintains mRNA stability in the cytoplasm.

Original Research

12 April 2021

Identification of Expression Patterns and Potential Prognostic Significance of m5C-Related Regulators in Head and Neck Squamous Cell Carcinoma

Zhenyuan Han

, 3 more and

Zhen Tian

3,125 views

16 citations

2) Tumor immuno microenvironment (TIME) (B cells, dendritic cells, T cells, NK cells, fibroblast) activated by m6A regulator and induces immunotherapy resistance for cancer cells. 3) Radiation induces m6a regulator and stabilizes mRNA of cancer stem cell. In the figure, the small upward black arrow indicates “upregulation” and the downward black arrow indicates “down regulation”.

Mini Review

25 February 2021

The Impact of m6A RNA Modification in Therapy Resistance of Cancer: Implication in Chemotherapy, Radiotherapy, and Immunotherapy

Omprakash Shriwas

, 2 more and

Rupesh Dash

13,040 views

57 citations

(A) The Kaplan–Meier survival analysis of HCC cases with different miRNA expression level in The Cancer Genome Atlas (TCGA). (B) The Kaplan–Meier survival analysis of HCC cases with different miRNA expression level in GSE31384. (C) The Kaplan–Meier survival analysis of HCC cases with different expression level of hsa-miR-139-5p and YTHDF1 in TCGA. (D) Construction of hub circRNA regulatory network based on hsa-miR-139-5p/YTHDF1 axis. The diamond, rectangle and ellipse indicated circRNA, miRNA, and mRNA, respectively. Yellow and light green represented up- and down-regulated, respectively.

Original Research

23 February 2021

Analysis and Validation of circRNA-miRNA Network in Regulating m6A RNA Methylation Modulators Reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis Involving the Proliferation of Hepatocellular Carcinoma

Fanwu Chi

, 1 more and

Yuhan Chen

6,025 views

42 citations

Original Research

23 February 2021

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

Xiaonan Liu

, 3 more and

Shuhui Song

6,765 views

19 citations

Review

01 February 2021

Methyladenosine Modification in RNAs: Classification and Roles in Gastrointestinal Cancers

Qinghai Li

, 1 more and

Guohui Wan

6,133 views

15 citations

Original Research

29 January 2021

RNA m6A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer

Lin Yang

, 5 more and

Wei-Min Tong

6,177 views

10 citations

Review

24 February 2021

m6A Modifications Play Crucial Roles in Glial Cell Development and Brain Tumorigenesis

Jing Wang

, 1 more and

Tao Sun

5,407 views

11 citations

m6A methylation occurs through methyltransferase complexes: mainly by METTL3, METTL14 and WTAP complex (cofactors: KIAA1429, RBM15, ZC3CH3, and HAIKAI). The m6A modification is removed by demethylase FTO or ALKBH5. Reader proteins recognize m6A and determine target RNA fate (42).

Review

21 January 2021

Regulation of Gene Expression Associated With the N6-Methyladenosine (m6A) Enzyme System and Its Significance in Cancer

Shuoran Tian

, 3 more and

Qi Chen

8,751 views

40 citations

(A) The results of differential expression analysis of IL-37 between the lung adenocarcinoma and matched tumor normal tissues. Data are mean ± SEM (n = 48 per group); (B) The expression of IL-37 in different LAD cell lines. Data are mean ± SEM (n = 6 per group); (C) The degree of IL-37 downregulation was greater in stages I and II than in stages 0 in primary LAC tumors. Data are mean ± SEM (n = 10 per group); (D) Results of analysis from starBase. Data are mean ± SEM. *P < 0.05.

Original Research

08 January 2021

IL-37 Confers Anti-Tumor Activity by Regulation of m6A Methylation

Xiaofeng Mu

, 9 more and

Ye Wang

5,448 views

18 citations

(A) For the 16 lncRNAs highly expressed in GBM patients, the Kaplan-Meier overall survival curve of the subjects with high lncRNA expression is significantly longer than the subjects with low lncRNA expression. (B) For the two lncRNAs lowly expressed in GBM patients, the Kaplan-Meier overall survival curve of the subjects with low lncRNA expression is significantly longer than the subjects with high lncRNA expression. (C) The forest plot for the results of univariate Cox regression analysis in LGG. (D) The relationship between the partial likelihood deviance and the penalty coefficient λ value. The log (λ) is equal to about 2.5 when the partial likelihood deviance reaches its minimum value. (E) The LASSO regression for calculating the coefficient of each lncRNA. There are four lncRNAs with non-zero coefficients when the log (λ) is equal to 2.5. (F) The ROC curve shows the reliability of the risk score.

Original Research

08 January 2021

Genome-Wide Identification and Analysis of the Methylation of lncRNAs and Prognostic Implications in the Glioma

Yijie He

, 2 more and

Zhijie Han

4,110 views

5 citations

Review

16 November 2020

FTO – A Common Genetic Basis for Obesity and Cancer

Ning Lan

, 6 more and

Wenzhen Yuan

In recent years, the prevalence of obesity and cancer have been rising. Since this poses a serious threat to human health, the relationship between the two has attracted much attention. This study examined whether fat mass and obesity-associated (FTO) genes are linked, taking into account a Genome-wide Association Study (GWAS) that revealed multiple single nucleotide polymorphism sites (SNPs) of the FTO gene, indicating an association between obesity and cancer in different populations. FTO proteins have been proved to participate in adipogenesis and tumorigenesis with post-transcriptional regulation of downstream molecular expression or through the target of the mammalian target protein rapamycin (mTOR). FTO inhibitors have also been found to share anti-obesity and anti-cancer effects in vivo. In this review, we comprehensively discuss the correlation between obesity and cancer by measuring FTO gene polymorphism, as well as the molecular mechanism involved in these diseases, emphasizing FTO as the common genetic basis of obesity and cancer.

43,929 views

111 citations

(A) Dynamic DNA and RNA modifications. DNA methyltransferases (DNMTs) including de novo methyltransferases DNMT3A, DNMT3B and maintenance methyltransferase DNMT1 convert unmodified cytosine (C) to 5‑methylcytosine (5mC). 5mC can be converted to 5‑hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) proteins‑mediated oxidation. TET proteins also catalyze the oxidation of 5hmC to 5‑formylcytosine (5fC) and 5‑carboxylcytosine (5caC). 5fC and 5caC can be further excised by thymine DNA glycosylase (TDG) coupled with base excision repair (BER) to generate unmodified cytosine. N6-methyladenosine (m6A) in mRNA is installed by methyltransferase-like protein 3 (METTL3) and METTL14, and erased by fat mass and obesity-associated protein (FTO) and α‑ketoglutarate-dependent dioxygenase alkB homologue 5 (ALKBH5). m6A can be further oxidized to N6-hydroxymethyladenosine (hm6A) and N6-formyladenosine (f6A) sequentially by FTO. (B) Epigenetic modifications involve in kidney cancer. Epigenetic modifications regulate diverse signaling pathways including HIF and PI3K-AKT and involve in kidney cancer.

Review

13 November 2020

The Roles of Base Modifications in Kidney Cancer

Chunyue Feng

, 2 more and

Jianhua Mao

2,355 views

2 citations

Statistics for genes with m6A modifications in each sample. (A) Number of genes with m6A sites in three GC samples; (B) number of genes with m6A sites in three PCa samples; (C) number of genes in GC and PCa tissues. We detected 1,487 m6A genes in GC tissues and 1,230 genes in PCa tissues, respectively, 365 genes were comethylated in GC and PCa tissues, accounting for 15.52% of the total methylated genes; 1,122 and 865 genes were only methylated in GC and PCa tissues, respectively.

Original Research

04 November 2020

The N6-Methyladenosine Features of mRNA and Aberrant Expression of m6A Modified Genes in Gastric Cancer and Their Potential Impact on the Risk and Prognosis

Liang Sang

, 3 more and

Yuan Yuan

3,689 views

11 citations

Original Research

02 November 2020

IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism

Jian Pu

, 10 more and

Huamei Wei

8,142 views

116 citations

Original Research

05 October 2020

Prognosis Analysis and Validation of m6A Signature and Tumor Immune Microenvironment in Glioma

Shaojian Lin

, 6 more and

Meiqing Lou

Glioma is one of the most typical intracranial tumors, comprising about 80% of all brain malignancies. Several key molecular signatures have emerged as prognostic biomarkers, which indicate room for improvement in the current approach to glioma classification. In order to construct a more veracious prediction model and identify the potential prognosis-biomarker, we explore the differential expressed m⁶A RNA methylation regulators in 665 gliomas from TCGA-GBM and TCGA-LGG. Consensus clustering was applied to the m6A RNA methylation regulators, and two glioma subgroups were identified with a poorer prognosis and a higher grade of WHO classification in cluster 1. The further chi-squared test indicated that the immune infiltration was significantly enriched in cluster 1, indicating a close relation between m⁶A regulators and immune infiltration. In order to explore the potential biomarkers, the weighted gene co-expression network analysis (WGCNA), along with Least absolute shrinkage and selection operator (LASSO), between high/low immune infiltration and m⁶A cluster 1/2 groups were utilized for the hub genes, and four genes (TAGLN2, PDPN, TIMP1, EMP3) were identified as prognostic biomarkers. Besides, a prognostic model was constructed based on the four genes with a good prediction and applicability for the overall survival (OS) of glioma patients (the area under the curve of ROC achieved 0.80 (0.76–0.83) and 0.72 (0.68–0.76) in TCGA and Chinese Glioma Genome Atlas (CGGA), respectively). Moreover, we also found PDPN and TIMP1 were highly expressed in high-grade glioma from The Human Protein Atlas database and both of them were correlated with m6A and immune cell marker in glioma tissue samples. In conclusion, we construct a novel prognostic model which provides new insights into glioma prognosis. The PDPN and TIMP1 may serve as potential biomarkers for prognosis of glioma.

10,881 views

67 citations

HNRNPA2B1 promotes ESCC progression by regulation of fatty acid metabolism. (A) The genes correlated with HNRNPA2B1 expression in ESCA patients were analyzed using TCGA dataset and then the pathway of these genes via KEGG enrichment. (B) The mRNA levels of major enzymes in de novo fatty acid synthesis (FASN, ACLY, SCD1, and ACC1), fatty acid β-oxidation (MCAD and CPT1A), and fatty acid uptake (CD36 and FABP5) were detected in ECA109 and TE10 cells upon HNRNPA2B1 knockdown. (C) The correlations of HNRNPA2B1 expression with ACLY and ACC1 via online bioinformatics tool (http://gepia.cancer-pku.cn/) are analyzed. (D) Cellular neutral lipids were measured in ECA109 cells and TE10 cells upon HNRNPA2B1 knockdown by Nile red staining, Scale bars, 100 μm. (E,F) OA promoted ESCC cell proliferation, migration, and invasion, whereas knockdown of HNRNPA2B1 inhibited OA-induced ESCC cell proliferation, migration, and invasion. *P < 0.05, **P < 0.01, and ***P < 0.001.

Original Research

29 September 2020

m6A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1

Huimin Guo

, 7 more and

Xiaoping Zou

N6-methyladenosine (m⁶A) modification is the most abundant modification on eukaryotic RNA. In recent years, lots of studies have reported that m⁶A modification and m⁶A RNA methylation regulators were involved in cancer progression. However, the m⁶A level and its regulators in esophageal cancer (ESCA) remain poorly understood. In this study, we analyzed the expression of m⁶A regulators using The Cancer Genome Atlas data and found 14 of 19 m⁶A regulators are significantly increased in ESCA samples. Then we performed a univariate Cox regression analysis and LASSO (least absolute shrinkage and selection operator) Cox regression model to investigate the prognostic role of m⁶A regulators in ESCA, and the results indicated that a two-gene prognostic signature including ALKBH5 and HNRNPA2B1 could predict overall survival of ESCA patients. Moreover, HNRNPA2B1 is higher expressed in high-risk scores subtype of ESCA, indicating that HNRNPA2B1 may be involved in ESCA development. Subsequently, we confirmed that the level of m⁶A and HNRNPA2B1 was significantly increased in ESCA. We also found that HNRNPA2B1 expression positively correlated with tumor diameter and lymphatic metastasis of ESCA. Moreover, functional study showed that knockdown of HNRNPA2B1 inhibited the proliferation, migration, and invasion of ESCA. Mechanistically, we found that knockdown of HNRNPA2B1 inhibited the expression of de novo fatty acid synthetic enzymes, ACLY and ACC1, and subsequently suppressed cellular lipid accumulation. In conclusion, our study provides critical clues to understand the role of m⁶A and its regulators in ESCA. Moreover, HNRNPA2B1 functions as an oncogenic factor in promoting ESCA progression via up-regulation of fatty acid synthesis enzymes ACLY and ACC1, and it may be a promising prognostic biomarker and therapeutic target for human ESCA.

8,427 views

94 citations

Original Research

30 September 2020

Hematopoietic Gene Expression Regulation Through m6A Methylation Predicts Prognosis in Stage III Colorectal Cancer

Zheng Zhou

, 7 more and

Guoxiang Cai

3,122 views

3 citations

Original Research

14 July 2020

Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation

Yu Shi

, 10 more and

Yuee Teng

METTL3 suppressed metastatic ability in TNBC cells. (A) qRT-PCR was used to detect METTL3 expression in MDA-MB-231 and MDA-MB-468 cells transfected with si-NC or si-METTL3. 18S was used as an internal control. (B) Western blot was used to detect METTL3 expression in MDA-MB-231 and MDA-MB-468 cells transfected with si-NC or si-METTL3. α-tubulin was used as a loading control. (C,D) Transwell assay was used to detect the migration and invasion ability in MDA-MB-231 and MDA-MB-468 cells with METTL3 transient knockdown (left panels). Relative fold change was shown as the proportion of the number of control cells transfected with si-NC (right panels). Original magnification, 100×. (E) Adhesion assay was used to detect the adhesion ability of MDA-MB-231 and MDA-MB-468 cells with METTL3 transient knockdown (left panels). Relative fold change was shown as the proportion of the number of control cells transfected with si-NC (right panels). Original magnification, 100×. *P < 0.05, **P < 0.01. Error bars represent the mean ± SD of three independent experiments.

The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (METTL3) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown of METTL3 could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (COL3A1) was identified and verified as a target gene of METTL3. METTL3 could down-regulate the expression of COL3A1 by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved that METTL3 expression was negatively correlated with COL3A1 in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.