bims-rimeca 2022-04-17 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2022–04–17
24 papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Molecular subtypes of m6A RNA methylation modification patterns and their clinical significance in clear cell renal cell carcinoma.
RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m6A-YTHDF2-dependent manner.
N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability.
m6A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2.
METTL3 promotes prostate cancer progression by regulating miR-182 maturation in m6A-dependent manner.
Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in HNSCC.
FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms.
Comprehensive Analysis Revealed the Potential Implications of m6A Regulators in Lung Adenocarcinoma.
ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype.
Alteration of N6-Methyladenosine mRNA Methylation in a Human Stem Cell-Derived Cardiomyocyte Model of Tyrosine Kinase Inhibitor-Induced Cardiotoxicity.
Emerging Roles and Mechanism of m6A Methylation in Cardiometabolic Diseases.
METTL3-stabilized lncRNA SNHG7 accelerates glycolysis in prostate cancer via SRSF1/c-Myc axis.
SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer.
Inducible and reversible RNA N6-methyladenosine editing.
Pathogenic roles of m6A modification in viral infection and virus-driven carcinogenesis.
Solution structure ensemble of human obesity-associated protein FTO reveals druggable surface pockets at the interface between the N- and C-terminal domain.
N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance.
Bioinformatics Analysis Identified Five Widely Expressed Genes Associated with Prognosis in Sarcoma.
m6A echoes with DNA methylation: Coordinated DNA Methylation and Gene Expression Data Analysis Identified Critical m6A Genes Associated with Asthma.
METTL3 Facilitates Tumor Progression by COL12A1/MAPK Signaling Pathway in Esophageal Squamous Cell Carcinoma.
A Novel m1A-Score Model Correlated With the Immune Microenvironment Predicts Prognosis in Hepatocellular Carcinoma.
Identification of Prognostic Markers of N6-Methylandenosine-Related Noncoding RNAs in Non-Small-Cell Lung Cancer.
Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms.
SLC2A1 is a Diagnostic Biomarker Involved in Immune Infiltration of Colorectal Cancer and Associated With m6A Modification and ceRNA.

Transl Cancer Res. 2022 Mar;11(3): 508-518

Molecular subtypes of m6A RNA methylation modification patterns and their clinical significance in clear cell renal cell carcinoma.

Bo Guan, Feng Ren, Weimin Shan, Shangrong Zhang.

   Background: In this study, we sought to investigate the association between N6-methyladenosine (m6A) RNA methylation-modification patterns and patient prognosis in clear cell renal cell carcinoma (ccRCC) and construct a ccRCC molecular signature according to expressions of m6A-related genes.
Methods: First, the clinical data and the transcriptomes of 530 patients with ccRCC were downloaded from The Cancer Genome Atlas (TCGA). The expression patterns of m6A-related genes were extracted, and the differences in m6A-modification patterns between normal and tumor renal tissues were analyzed. To explore the prognostic role of m6A-modification patterns a in ccRCC, the molecular subtypes of ccRCC were identified based on the expression patterns of the m6A-related genes, and survival rates in patients with the different subtypes were compared. According to expressions of m6A-related genes and clinical prognosis data, a prognostic molecular signature was constructed using least absolute shrinkage and selector operation (LASSO)-Cox regression analysis.
Results: Among the 13 m6A -related genes identified in this study, 8 (YTHDC1, YTHDF2, HNRNPC, METTL14, ZC3H13, FTO, YTHDC2, and YTHDF1) showed significant expression differences between normal and tumor renal tissues. The molecular subtypes of ccRCC identified according to their expression of the 13 m6A-related genes were associated with differential clinical outcomes.
Conclusions: Following TCGA data-mining, different molecular subtypes of ccRCC based on m6A RNA methylation patterns were found to have different prognoses. The molecular signature constructed according to the expression patterns of m6A-related genes could predict patient prognosis in ccRCC. We believe m6A RNA methylation modification is a potential therapeutic target and may play a crucial role in ccRCC.

Keywords:  N6-methyladenosine (m6A) RNA methylation modification; Renal cell carcinoma (RCC); molecular signature; molecular subtype

DOI:  https://doi.org/10.21037/tcr-22-117
Oncogene. 2022 Apr 14.

RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m6A-YTHDF2-dependent manner.

Zhen Tan, Si Shi, Jin Xu, Xiaomeng Liu, Yubin Lei, Bo Zhang, Jie Hua, Qingcai Meng, Wei Wang, Xianjun Yu, Chen Liang.

RNA N6-methyladenosine (m6A) is an emerging regulator of mRNA modifications and represents a novel player in tumorigenesis. Although it has functional significance in both pathological and physiological processes, the role of m6A modification in pancreatic ductal cancer (PDAC) remains elusive. Here, we showed that high fat mass and obesity-associated gene (FTO) expression was associated with a poor prognosis in PDAC patients and that suppression of FTO expression inhibited cell proliferation. Here, m6A sequencing (m6A-seq) was performed to screen genes targeted by FTO. The effects of FTO stimulation on the biological characteristics of pancreatic cancer cells, including proliferation and colony formation, were investigated in vitro and in vivo. The results indicate that FTO directly targets platelet-derived growth factor C (PDGFC) and stabilizes its mRNA expression in an m6A-YTHDF2-dependent manner. m6A-methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to validate the specific binding of FTO to PDGFC. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting cell growth. Overall, our study reveals that FTO downregulation leads to increased m6A modifications in the 3' UTR of PDGFC and then modulates the degradation of its transcriptional level in an m6A-YTHDF2-dependent manner, highlighting a potential therapeutic target for PDAC treatment and prognostic prediction.

DOI: https://doi.org/10.1038/s41388-022-02306-w
Cell Death Discov. 2022 Apr 09. 8(1): 184

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability.

Libin Zou, Wenbin Chen, Xumin Zhou, Taowei Yang, Junqi Luo, Zining Long, Jun Wu, Daojun Lv, Xiangming Mao, Shengren Cen.

The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.

DOI: https://doi.org/10.1038/s41420-022-01003-7
Epigenetics. 2022 Apr 11. 1-15

m6A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2.

Wei Wang, Ying He, Lu-Lu Zhai, Long-Jiang Chen, Li-Chao Yao, Lun Wu, Zhi-Gang Tang, Jin-Zhuo Ning.

  Pancreatic cancer (PC) is one of the most fatal cancers with a very poor prognosis. Here, we found that N6-methyladenosine (m6A) RNA demethylase fat mass and obesity-related protein (FTO) promote the growth, migration and invasion of PC. FTO expression level is increased in human PC and is associated with poor prognosis of PC patients. Knockdown of FTO increases m6A methylation of TFPI-2 mRNA in PC cells, thereby increasing mRNA stability via the m6A reader YTHDF1, resulting in up-regulation of TFPI-2 expression, and inhibits PC proliferation, colony formation, sphere formation, migration and invasion in vitro, as well as tumour growth in vivo. Rescue assay further confirms that FTO facilitates cancer progression by reducing the expression of TFPI-2. Mechanistically, FTO promotes the progression of PC at least partially through reducing m6A/YTHDF1 mediated TFPI-2 mRNA stability. Our findings reveal that FTO, as an m6A demethylase, plays a critical role in promoting PC growth, migration and invasion, suggesting that FTO may be a potential therapeutic target for treating PC.

Keywords:  FTO; TFPI-2; m6A; pancreatic cancer; progression

DOI:  https://doi.org/10.1080/15592294.2022.2061117
Andrologia. 2022 Apr 12. e14422

METTL3 promotes prostate cancer progression by regulating miR-182 maturation in m6A-dependent manner.

Dawei Wang, Xiaojing Wang, Baoxing Huang, Yang Zhao, Weichao Tu, Xingwei Jin, Yuan Shao, Yu Zhu, Guoliang Lu.

  METTL3 was known to run through the whole cycle of RNA. It relied on m6A modification in the mRNAs of cancer-related genes to regulate tumour progression. The development of prostate cancer cells could be promoted by METTL3 via hedgehog pathway. Recent studies had shown that the effect of METTL3 on non-coding RNA was mainly dependent on the modification of m6A. However, it is still unknown whether METTL3 promotes tumour development through this mechanism in prostate cancer. The expression of METTL3 in prostate cancer tissues and cells was analysed by qRT-PCR and Western blot assays. CCK-8 assay, colony formation assay, wound-healing assay and transwell assays were conducted to detect the impact of METTL3 on cell proliferation, migration and invasion. Nude mice tumour models were built to evaluate the role of METTL3 in tumorigenesis. N6-methyladenosine (m6A) RNA immunoprecipitation assay (MeRIP) and co-immunoprecipitations assays were performed to verified that METTL3 upregulated the m6A level, interacted with microprocessor protein DGCR8, recognized the m6A modification of pre-miR-182 to regulate its maturation.METTL3 was highly expressed in prostate cancer, and knockdown of METTL3 significantly inhibited cell proliferation, migration, invasion and tumorigenesis, while overexpression of METTL3 promoted cell proliferation, migration, invasion and tumorigenesis in PCa. In addition, we found that METTL3 upregulating the level of m6A, and interacted with DGCR8 to recognize the m6A modification of pre-miR-182 to regulate its splicing and maturation and promote the high expression of miRNA. Our study suggests that METTL3 could be used in targeted therapies for PCa.

Keywords:  METTL3; m6A; miR-182; prostate cancer

DOI:  https://doi.org/10.1111/and.14422
Cancer Sci. 2022 Apr 11.

Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in HNSCC.

Xi Chen, Yunxia Liu, Dongyuan Sun, Rongqi Sun, Xiaoxiao Wang, Minmin Li, Ning Song, Jicheng Ying, Tao Guo, Yingying Jiang.

  Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor in the oral and maxillofacial regions, and long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of HNSCC. The lncRNA lnc-H2AFV-1 was found to be upregulated in HNSCC tissues; however, the function of lnc-H2AFV-1 in regulating HNSCC proliferation and the potential molecular mechanism is unclear. The present study evaluated the expression of lnc-H2AFV-1 in HNSCC tissues using quantitative real-time PCR (qPCR) and associated abundant lnc-H2AFV-1 expression with tumor size. Functionally, lnc-H2AFV-1 significantly promoted the proliferation of HNSCC cells in vitro and in vivo. Quantified N6-methyladenosine (m6A) RNA methylation and dot blot assays revealed that total m6A methylation in HNSCC cells was accompanied by lnc-H2AFV-1 expression. Western blotting showed that the expression of methyltransferase-like (METTL) 3 and METTL14 was consistent with that of lnc-H2AFV-1, whereas the expression of demethylase fat mass and obesity-associated (FTO) was contrary to that of lnc-H2AFV-1. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-qPCR revealed that lnc-H2AFV-1 overexpression led to the elevated expression and maximal m6A methylation of intraflagellar transport (IFT) 80 in HNSCC. In addition, METTL3/14 knockdown decreased IFT80 expression. Thus, our findings suggested that lnc-H2AFV-1 might be a biomarker that alters m6A modification by regulating the m6A methylases METTL3/14 and FTO, and then mediating downstream target IFT80 to promote HNSCC progression.

Keywords:  N6-methyladenosine; cell growth; head and neck squamous cell carcinoma; lnc-H2AFV-1; long noncoding RNA

DOI:  https://doi.org/10.1111/cas.15366
Int J Mol Sci. 2022 Mar 30. pii: 3800. [Epub ahead of print]23(7):

FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms.

Sarah Kassem Azzam, Habiba Alsafar, Abdulrahim A Sajini.

  Fat mass and obesity-associated protein (FTO) is the first reported RNA N6-methyladenosine (m6A) demethylase in eukaryotic cells. m6A is considered as the most abundant mRNA internal modification, which modulates several cellular processes including alternative splicing, stability, and expression. Genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) within FTO to be associated with obesity, as well as cancer including endometrial cancer, breast cancer, pancreatic cancer, and melanoma. Since the initial classification of FTO as an m6A demethylase, various studies started to unravel a connection between FTO's demethylase activity and the susceptibility to obesity on the molecular level. FTO was found to facilitate adipogenesis, by regulating adipogenic pathways and inducing pre-adipocyte differentiation. FTO has also been investigated in tumorigenesis, where emerging studies suggest m6A and FTO levels are dysregulated in various cancers, including acute myeloid leukemia (AML), glioblastoma, cervical squamous cell carcinoma (CSCC), breast cancer, and melanoma. Here we review the molecular bases of m6A in tumorigenesis and adipogenesis while highlighting the controversial role of FTO in obesity. We provide recent findings confirming FTO's causative link to obesity and discuss novel approaches using RNA demethylase inhibitors as targeted oncotherapies. Our review aims to confirm m6A demethylation as a risk factor in obesity and provoke new research in FTO and human disorders.

Keywords:  N6-methyladenosine (m6A); adipogenesis; cancer; fat mass and obesity-associated (FTO) protein; obesity; tumorigenesis

DOI:  https://doi.org/10.3390/ijms23073800
Front Mol Biosci. 2022 ;9 806780

Comprehensive Analysis Revealed the Potential Implications of m6A Regulators in Lung Adenocarcinoma.

Lingling Xie, Rongyang Dai, Xudong Wang, Guangfei Xie, Zhihua Gao, Xinxin Xu.

  Background: The biological significance of RNA N6-methyladenosine (m6A) decoration in tumorigenicity and progression has been highlighted in recent studies, but whether m6A modification plays a potential role in tumor microenvironment (TME) formation and immune regulation in lung adenocarcinoma (LUAD) remains unclear. Methods: m6A modification features were evaluated by analyzing the multi-omics features of 17 m6A regulators in over 1900 LUAD samples, and at the same time, the correlation between these modification patterns and TME characteristics was analyzed. An m6A score signature-based principal component analysis (PCA) algorithm was constructed to assess the prognosis and responses of individual patients to immunotherapeutic and targeted therapies. Results: Three different m6A modification patterns were determined in 1901 LUAD samples, which were found to be related to diverse clinical outcomes via different biological pathways. Based on the m6A score extracted from the m6A-associated signature genes, LUAD patients were separated into high- and low-m6A score groups. It was discovered that patients with high m6A scores had longer survival, lower tumor mutation loads, and low PD-L1/PDCD1/CTLA4/TAG3 expression level. In addition, LUAD patients with high m6A scores displayed lower IC50 to some targeted drugs, including nilotinib, erlotinib, imatinib, and lapatinib. Conclusion: m6A modification was significantly associated with the TME and clinical outcomes. These findings may help gain more insights into the role of m6A decoration in the molecular mechanism of LUAD, thus facilitating the development of more effective personalized treatment strategies.

Keywords:  immunotargeted therapy; lung adenocarcinoma; m6A decoration; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2022.806780
Int J Biol Sci. 2022 ;18(6): 2235-2248

ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype.

Tingting Yu, Lan Yao, Hua Yin, Yao Teng, Mei Hong, Qiuling Wu.

  N6-methyladenosine (m6A) is the most prevalent modification to RNA in higher eukaryotes. ALKBH5 is an RNA demethylase that impacts RNA export and metabolism, and its aberrant expression is associated with the generation of tumours. In this study, we found that ALKBH5 was highly expressed in both primary CD138+ plasma cells isolated from multiple myeloma (MM) patients and MM cell lines. Downregulation of ALKBH5 inhibited myeloma cell proliferation, neovascularization, invasion and migration ability, and promoted the apoptosis in vivo and in vitro. MeRIP-seq identified the SAV1 gene as main target gene of ALKBH5. Inhibiting ALKBH5 in MM cells increased SAV1 m6A levels, decreased SAV1 mRNA stability and expression, suppressed the stem cell related HIPPO-pathway signalling and ultimately activates the downstream effector YAP, exerting an anti-myeloma effect. Additionally, MM stem cell phenotype was suppressed in ALKBH5-deficient cells and the expression of pluripotency factors NANOG, SOX2 and OCT4 were also decreased. Altogether, our results suggest that ALKBH5 acts as an oncogene in MM and might serve as an attractive potential biomarker and therapeutic target.

Keywords:  ALKBH5; Apoptosis; Cell proliferation; Hippo pathway; m6A; multiple myeloma; multiple myeloma stem cell

DOI:  https://doi.org/10.7150/ijbs.64943
Front Cardiovasc Med. 2022 ;9 849175

Alteration of N6-Methyladenosine mRNA Methylation in a Human Stem Cell-Derived Cardiomyocyte Model of Tyrosine Kinase Inhibitor-Induced Cardiotoxicity.

Yan Ma, Xian Liu, Yiming Bi, Tianhu Wang, Cheng Chen, Yabin Wang, Dong Han, Feng Cao.

   Background: N6-methyladenosine (m6A) plays important roles in various cardiovascular diseases (CVDs), including cardiac hypertrophy and heart failure. Sunitinib (SUN) is a tyrosine kinase inhibitor (TKI) that is widely used in the treatment of different types of solid and blood tumors, but its efficacy is restricted by a concomitant rise in cardiotoxicities. However, the methylation modification of m6A messenger RNA (mRNA) in cardiomyocytes treated with TKI has not been investigated.
Methods: The global m6A methylation level of SUN-induced cardiotoxicity was detected by m6A dot blot and colorimetric methylation assay. MeRIP-Seq (methylated RNA immunoprecipitation sequencing) and RNA-seq (RNA sequencing, input) were employed to depict the landscapes of transcriptome and epitranscriptome in TKI. Changes in major m6A-related enzymes were detected by qRT-PCR and Western blot. In addition, the effects of FTO on SUN-induced cardiotoxicity were evaluated by gain and loss of function studies.
Results: In this study, we observed that the m6A methylation level was significantly elevated in SUN-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and paralleled a positively correlated cellular damage level. Through a genome-wide analysis of m6A mRNA methylation by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and input RNA sequencing (RNA-seq), we identified a total of 2,614 peaks with significant changes, of which 1,695 peaks were significantly upregulated and 919 peaks were significantly downregulated. Quantitative reverse transcription PCR (RT-qPCR), immunofluorescence, and Western blotting revealed that the RNA demethylase fat mass and obesity-associated protein (FTO) was downregulated, whereas the RNA methylases methyltransferase-like 14 (METTL14) and wilms' tumor 1-associating protein (WTAP) were upregulated. Furthermore, gain- and loss-of-function studies substantiated that FTO is cardioprotective in TKI.
Conclusion: This study deciphered the methylation modification of m6A mRNA in hiPSC-CMs post-TKI treatment and determined that FTO may be a promising therapeutic target for TKI-induced cardiotoxicity.

Keywords:  FTO; N6-methyladenosine; cardiotoxicity; hiPSC-CMs; tyrosine kinase inhibitor (TKI)

DOI:  https://doi.org/10.3389/fcvm.2022.849175
Cells. 2022 Mar 24. pii: 1101. [Epub ahead of print]11(7):

Emerging Roles and Mechanism of m6A Methylation in Cardiometabolic Diseases.

Zujie Xu, Binbin Lv, Ying Qin, Bing Zhang.

  Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.

Keywords:  N6-Methyladenosine (m6A); RNA methylation; cardiometabolic diseases (CMDs)

DOI:  https://doi.org/10.3390/cells11071101
Exp Cell Res. 2022 Apr 08. pii: S0014-4827(22)00142-2. [Epub ahead of print] 113149

METTL3-stabilized lncRNA SNHG7 accelerates glycolysis in prostate cancer via SRSF1/c-Myc axis.

Jun Liu, Jun-Fang Yuan, Yu-Zhong Wang.

   BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as novel players in cancer metabolism. lncRNA small nucleolar RNA host gene 7 (SNHG7) plays an oncogenic role in prostate cancer (PCa). However, the role and mechanism of SNHG7 in PCa metabolism remain largely undefined.
METHODS: A cohort of 30 PCa tumors and their counterparts were collected. qRT-PCR was employed to detect target gene expression and RNA stability. CCK-8 assay was used to assess cell viability. N6-methyladenosine (m6A) level was measured by a commercial kit. Cell glycolysis was evaluated by measuring glucose uptake, lactate, ATP production and Extracellular acidification rate (ECAR). Bioinformatics analysis and RNA immunoprecipitation (RIP) assay were used to verify the interactions among SNHG7, serine/arginine-rich splicing factor 1 (SRSF1) and c-Myc.
RESULTS: SNHG7 and c-Myc were highly expressed in PCa tissues and cells. Methyltransferase-like 3 (METTL3)-mediated m6A modification of SNHG7 and enhanced its stability. Silencing of SNHG7 suppressed proliferation and glycolysis in PCa cells. Mechanistically, SNHG7 regulated c-Myc via interacting with SRSF1. Gain- and loss-of function experiments revealed that SNHG7 promoted glycolysis via SRSF1/c-Myc axis in PC-3 and DU-145 cells.
CONCLUSION: METTL3-stabilized lncRNA SNHG7 accelerates glycolysis in PCa via SRSF1/c-Myc axis and inspires the understanding of m6A roles in lncRNA metabolism and tumor progression.

Keywords:  Glycolysis; METTL3; Prostate cancer; SNHG7; SRSF1; c-Myc

DOI:  https://doi.org/10.1016/j.yexcr.2022.113149
Cell Death Discov. 2022 Apr 13. 8(1): 199

SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer.

Jiazhu Sun, Xueyou Ma, Yufan Ying, Weiyu Wang, Haixiang Shen, Song Wang, Haiyun Xie, Jiahe Yi, Weitao Zhan, Jiangfeng Li, Ben Liu.

Previous research evidence suggests that microRNAs (miRNAs) play an indispensable role in onset and progression of bladder cancer (BCa). Here, we explored the functions and mechanisms of miR-5581-3p in BCa. miR-5581-3p, as a tumor suppressor in BCa, was detected at a lower expression level in BCa tissue and cells in contrast with the non-malignant bladder tissue and cells. Over-expression of miR-5581-3p remarkably dampened the migration and proliferation of BCa in vitro and in vivo. SMAD3 and FTO were identified as the direct targets of miR-5581-3p by online databases prediction and mRNA-seq, which were further verified. SMAD3 as a star molecule in modulating EMT progress of BCa had been formulated in former studies. Meanwhile, FTO proved as an N6-methyladenosine (m6A) demethylase in decreasing m6A modification was confirmed to regulate the migration and proliferation in BCa. In addition, we conducted rescue experiments and confirmed overexpressing miR-5581-3p partially rescued the effects of the overexpressing SMAD3 and FTO in BCa cells. In conclusion, our studies exhibit that miR-5581-3p is a novel tumor inhibitor of BCa.

DOI: https://doi.org/10.1038/s41420-022-01010-8
Nat Commun. 2022 Apr 12. 13(1): 1958

Inducible and reversible RNA N6-methyladenosine editing.

Huaxia Shi, Ying Xu, Na Tian, Ming Yang, Fu-Sen Liang.

RNA modifications, including N6-methyladenosine (m6A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Methods enabling temporal and transcript/locus-specific editing of specific RNA modifications are essential, but still limited, to dissect the dynamic and context-dependent functions of these epigenetic modifications. Here, we develop a chemically inducible and reversible RNA m6A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods. We show that m6A editing can be temporally controlled at specific sites of individual RNA transcripts by the addition or removal of the CIP inducer, abscisic acid (ABA), in the system. By incorporating a photo-caged ABA, a light-controlled version of m6A editing platform can be developed. We expect that this platform and strategy can be generally applied to edit other RNA modifications in addition to m6A.

DOI: https://doi.org/10.1038/s41467-022-29665-y
Endocr Metab Immune Disord Drug Targets. 2022 Apr 12.

Pathogenic roles of m6A modification in viral infection and virus-driven carcinogenesis.

Jia-Feng Wang, Wei Cai, Fen-Sheng Qiu, Chen-Huan Yu.

  N6-methyladenosine (m6A) is a prevalent modification of RNA in eukaryotes, bacteria, and viruses. It is highly conserved and can affect the structure, localization, and biology functions of RNA. In recent years, multiple m6A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses. This modification occurs commonly during the primary infection and is dynamically regulated by a methyltransferase (writers), demethylase (eraser) and m6A-binding proteins (readers) within the host cells. The abnormal m6A modification not only affects the replication of pathogenic viruses and host immune response but also contributes to the pathogenesis of virus-induced cancers. In this review, we highlight recent advances on the mechanism of m6A modification on viral replication, host immune response and carcinogenesis to provide a novel insight for epigenetic prevention of viral infection and virus-driven carcinogenesis.

Keywords:  Carcinogenesis; Immune escape; Transcript stability; Viral replication; Virus-driven carcinogenesis; m6A modification

DOI:  https://doi.org/10.2174/2772432817666220412112759
J Biol Chem. 2022 Apr 06. pii: S0021-9258(22)00347-7. [Epub ahead of print] 101907

Solution structure ensemble of human obesity-associated protein FTO reveals druggable surface pockets at the interface between the N- and C-terminal domain.

Balabhadra Khatiwada, Trang T Nguyen, Jeffrey A Purslow, Vincenzo Venditti.

  The fat-mass and obesity-associated FTO protein catalyzes demethylation of the N6-methyladenosine (m6A), an epigenetic mark that controls several metabolic pathways by modulating the transcription, translation, and cellular localization of RNA molecules. Since the discovery that its overexpression links to the development of obesity and cancer, FTO has been the target of several screening campaigns and structure-based drug design efforts. Although several FTO inhibitors have been generated, these often lack potency or selectivity. Herein, we investigate the structure and dynamics of human FTO in solution. We show that the structure of the catalytic N-terminal domain is unstable in the absence of the C-terminal domain, which explains why the isolated N-terminal domain is incompetent for catalysis and suggests the domain interaction represents a target for the development of specific inhibitors. Then, by using NMR relaxation measurements, we show that the interface between the FTO structural domains, the active site, and several peripheral loops undergo conformational dynamics on both the ps-ns and μs-ms timescales. Consistent with this, we found that the backbone amide residual dipolar couplings (RDCs) measured for FTO in phage pf1 are inconsistent with the static crystal structure of the enzyme. Finally, we generated a conformational ensemble for apo FTO that satisfies the solution NMR data by combining the experimental RDCs with accelerated molecular dynamics (aMD) simulations. Altogether, the structural ensemble reported in this work provides an atomic-resolution model of apo FTO and reveals transient surface pockets at the domain interface that represent potential targets for the design of allosteric inhibitors.

Keywords:  NMR; RNA demethylase; accelerated MD; drug screening; invisible state; protein dynamic; protein folding

DOI:  https://doi.org/10.1016/j.jbc.2022.101907
Mil Med Res. 2022 Apr 14. 9(1): 19

N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance.

Xian Lin, Feng Wang, Jian Chen, Jing Liu, Yi-Bin Lin, Li Li, Chuan-Ben Chen, Qin Xu.

   BACKGROUND: Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study, we determined the relevant players and role of N6-methyladenine (m6A) RNA methylation in cervical cancer progression.
METHODS: The roles of m6A RNA methylation and centromere protein K (CENPK) in cervical cancer were analyzed using bioinformatics analysis. Methylated RNA immunoprecipitation was adopted to detect m6A modification of CENPK mRNA. Human cervical cancer clinical samples, cell lines, and xenografts were used for analyzing gene expression and function. Immunofluorescence staining and the tumorsphere formation, clonogenic, MTT, and EdU assays were performed to determine cell stemness, chemoresistance, migration, invasion, and proliferation in HeLa and SiHa cells, respectively. Western blot analysis, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter, cycloheximide chase, and cell fractionation assays were performed to elucidate the underlying mechanism.
RESULTS: Bioinformatics analysis of public cancer datasets revealed firm links between m6A modification patterns and cervical cancer prognosis, especially through ZC3H13-mediated m6A modification of CENPK mRNA. CENPK expression was elevated in cervical cancer, associated with cancer recurrence, and independently predicts poor patient prognosis [hazard ratio = 1.413, 95% confidence interval = 1.078 - 1.853, P = 0.012]. Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo (P < 0.001). We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK with β-catenin, which promoted β-catenin expression and nuclear translocation, facilitated p53 ubiquitination, and led to activation of Wnt/β-catenin signaling, but suppression of the p53 pathway. This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness, DNA damage repair pathways necessary for cisplatin/carboplatin resistance, epithelial-mesenchymal transition involved in metastasis, and DNA replication that drove tumor cell proliferation.
CONCLUSIONS: CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.

Keywords:  Centromere protein K; Cervical cancer; Chemoresistance; N 6-methyladenosine; Stemness

DOI:  https://doi.org/10.1186/s40779-022-00378-z
Int J Gen Med. 2022 ;15 3711-3725

Bioinformatics Analysis Identified Five Widely Expressed Genes Associated with Prognosis in Sarcoma.

Bizhi Tu, Yaya Jia, Jun Qian.

   Background: Human sarcomas (SARC) are a group of malignant tumors that originated from mesenchymal lineages with more than 60 subtypes. However, potential biomarkers for the diagnosis and prognosis of SARC remain to be investigated.
Methods: We obtained three GSE raw matrix files (GSE39262, GSE21122, GSE48418) that related to various subtypes of sarcoma from the public GEO database and explored the widely differential expression genes in three obtained GSE files. Then common differential expression genes (CDGEs) were identified. We analyzed the correlation between the expression of the top five interacted genes of CDEGs and genome-wide differences, prognosis, genetic mutation, functional enrichment, immune infiltration, immune checkpoint, and marker genes' expression of N6-methyladenosine (m6A) modification in SARC patients. Besides, a prognostic nomogram was constructed to predict the survival of SARC patients.
Results: Among the three GSE files, 42 CDGEs were identified, and the top five interacted genes were ASPM, CCNB2, PRC1, AURKA, and SCM2. The expression levels of the five genes were higher in the SARC group than that in the normal group. The transcriptional level of CCNB2, PRC, and SCM2 was correlated to the worse survival of SARC. The constructed nomogram that combined CNB2, PRC1, and SCM2 showed a fairly good incredibility in predicting the survival of SARC (C-index: 0.711). Furthermore, the five genes were widely involved in immune infiltration, immune checkpoint, and m6A modification. In addition, we found a minor survival-related mutation rate (9%) of the five identified genes in SARC patients (p < 0.05).
Conclusion: The results suggested the five identified genes widely participated in the prognosis, immune infiltration, immune checkpoint, and m6A modification of SARC patients. This study provided a theoretical basis for the research about the correlation between the level of five identified genes and sarcoma, but the further mechanism needs to be verified by experiments.

Keywords:  ASPM; AURKA; CCNB2; PRC1; SCM2; bioinformatics; differential expression gene; prognostic values; sarcoma

DOI:  https://doi.org/10.2147/IJGM.S352048
Gene. 2022 Apr 11. pii: S0378-1119(22)00276-1. [Epub ahead of print] 146457

m6A echoes with DNA methylation: Coordinated DNA Methylation and Gene Expression Data Analysis Identified Critical m6A Genes Associated with Asthma.

Bi-Wen Mo, Xiao-Mang Li, Shen-Mei Li, Bo Xiao, Jie Yang, Hui-Min Li.

  Asthma is a chronic inflammatory disease that involves complex gene-environment interactions. Methylation of nucleotides, such as 5-methylcytosine (5mC) in DNA and N6-methyladenosine (m6A) in mRNA, carries important information for gene regulation. Our study screened m6A genes and genes associated with asthma from the Gene Expression Omnibus (GEO) databases GSE63383, GSE119580, GSE38003, GSE34313, GSE13168, and GSE35643. GSE52778, GSE35643, GSE40996, and GSE64744), and DNA methylation data from GSE85568 and GSE146377. We screened out 6 m6A related genes (FTO, IGF2BP2, RBM15, RBMX, WTAP, and YTHDC1) that were significantly dysregulated in asthma or proinflammatory conditions. A correlation study showed a high correlation between m6A genes and gene pairs such as WTAP, IL7R, and TLR2; RBMX, SLC22A4, IL33, TNC, FLG, and IL6R (|r| ≥ 0.8). Following DNA methylation dataset analysis, we proposed several DNA methylation-m6A modification asthma-related gene axes such as cg19032951/cg15153914-IGF2BP2-SMAD3. Interestingly, several target genes, such as SMAD3, possess the ability to participate in DNA methylation processes, which may reciprocally regulate the expression of m6A genes and form a closed-loop regulation axis. Some classic DNA methylation-related genes, such as TET1, UHRF1, and ZBTB4, were also involved. We identified an integrated profile of m6A gene expression in asthma and proposed a novel potential interplay between DNA methylation and m6A modification in asthma pathogenesis. Using the CMAP database, we found that resveratrol may target these dysregulated m6A genes, and therefore may serve as a potential therapeutic agent for asthma.

Keywords:  Asthma; Closed-loop regulation; DNA methylation; GEO database; m6A

DOI:  https://doi.org/10.1016/j.gene.2022.146457
J Cancer. 2022 ;13(6): 1972-1984

METTL3 Facilitates Tumor Progression by COL12A1/MAPK Signaling Pathway in Esophageal Squamous Cell Carcinoma.

Jiali Li, Zhenhua Li, Yanzhao Xu, Chao Huang, Baoen Shan.

  Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive tumors in the world. m6A modification has been implicated to play an important role in many biological progressions. METTL3 as the main methyltransferase has been found in many cancers, including ESCC. Here, we investigated the underlying mechanism of METTL3 in the development of ESCC. Methods: Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) and western blot were used to detect METTL3 expression. To evaluate the function of METTL3, MTS, colony formation, scratch wound healing assay, and transwell and invasion assays were performed. To find out the downstream target of METTL3, mRNA sequencing (mRNA-seq) was conducted. GO and KEGG functional enrichment analyses were carried out to predict possible biological processes and signaling pathways. qRT-PCR and western blot were performed to identify the expression of COL12A1 and the phosphorylation status of RAF, MRK and ERK. Cotransfection of small interfering RNA (for METTL3 silence) with plasmid (for overexpression of COL12A1) and the following gain- and loss-of-function experiments were performed to detect the target gene function of COL12A1 in progression of ESCC mediated by METTL3. Results: Using TCGA database, higher METTL3 expression was found in ESCC tissues. Moreover, we found that METTL3 was significantly increased in ESCC patient tissues compared with normal tissues and correlated with poor prognosis. The expression of METTL3 in ESCC cell lines was assessed. The gain- and loss-of-function indicates that METTL3 promotes cell proliferation, migration and invasion. Additionally, we confirmed that METTL3 can promote the expression of COL12A1 and upregulate the phosphorylation of RAF, MER and ERK, and moreover COL12A1 can restrain siMETTL3-mediated inhibition of proliferation, migration and invasion in ESCC. Conclusion: Our study revealed that METTL3 may have an oncogenic role, facilitating the ESCC progression and metastasis by COL12A1/MAPK signaling pathway.

Keywords:  COL12A1; MAPK; METTL3; esophageal squamous cell carcinoma (ESCC); invasion; proliferation

DOI:  https://doi.org/10.7150/jca.66830
Front Immunol. 2022 ;13 805967

A Novel m1A-Score Model Correlated With the Immune Microenvironment Predicts Prognosis in Hepatocellular Carcinoma.

Mingxing Zhao, Shen Shen, Chen Xue.

  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.

Keywords:  HCC; biomarker; m1A modification; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.805967
J Oncol. 2022 ;2022 3657349

Identification of Prognostic Markers of N6-Methylandenosine-Related Noncoding RNAs in Non-Small-Cell Lung Cancer.

Zexin Zhang, Jing Li, Ke Lu, Wenfeng Wu, Ziyi Huang, Chi Zhang, Wei Guo, Jiayin Li, Lizhu Lin.

Background: Non-small-cell lung cancer (NSCLC) is a major type of lung carcinoma that threatens the health and life of humans worldwide. We aimed to establish an n6-methyladenosine (m6A)-relevant ncRNA model to effectively evaluate the outcome of patients.
Methods: m6A-Related ncRNAs (lncRNA/miRNA) were acquired from the UCSC Xena database. Pearson's correlation analysis among 21 m6A regulatory factors and ncRNAs were implemented to explore m6A-relevant ncRNAs. Weighted gene co-expression network analysis (WGCNA) identified hub modules of gene associated with prognosis of NSCLC patients. Univariate Cox regression analysis identified 80 m6A-related ncRNAs. Least absolute shrinkage and selector operation (LASSO) filtered out redundant factors and established a risk score model (m6A-NSCLC) in the TCGA training data set. Validation of prognostic ability was performed using testing data sets from the TCGA database. We also conducted a correlation analysis among the risk score and different clinical traits. Both univariate and multivariate Cox analyses were combined to verify prognostic factors which have independent value, and a nomogram on the basis of m6A-NSCLC risk scores and clinical traits was constructed to assess the prognosis of patients. In addition, we screened differentially expressed genes (DEGs) based on different risk scores and performed enrichment analysis. Finally, 21 m6A regulators were detected to be differentially expressed between two risk groups.
Results: An m6A-NSCLC risk model with 18 ncRNAs was constructed. By comparison with low-risk patients, high-risk score patients had poor prognosis. The distribution of risk score in the tumor size and extent (T), number of near lymph nodes (N), clinical stage, sex, and tumor types was significantly different. The risk score could act as an independent prognostic factor with the nomogram assessing overall survival in NSCLC. DEGs inherent to cell movement and immune regulation were involved in NSCLC development. Furthermore, 18 of 21 m6A regulators were differentially expressed, implying their correlation to survival prognosis.
Conclusion: The m6A-NSCLC could be effectively utilized for evaluation of prognosis of patients.

DOI: https://doi.org/10.1155/2022/3657349
Sci Transl Med. 2022 Apr 13. 14(640): eabk2709

Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms.

Jia-Nan Wang, Fang Wang, Jing Ke, Zeng Li, Chuan-Hui Xu, Qin Yang, Xin Chen, Xiao-Yan He, Yuan He, Xiao-Guo Suo, Chao Li, Ju-Tao Yu, Ling Jiang, Wei-Jian Ni, Juan Jin, Ming-Ming Liu, Wei Shao, Chen Yang, Qian Gong, Hai-Yong Chen, Jun Li, Yong-Gui Wu, Xiao-Ming Meng.

The role of N6-methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterized the role of N6-adenosine-methyltransferase-like 3 (METTL3), whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor-α (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)-induced renal dysfunction, injury, and inflammation. Moreover, TAB3 [TGF-β-activated kinase 1 (MAP3K7) binding protein 3] was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 (insulin-like growth factor 2 binding protein 2) to its m6A-modified stop codon regions. The proinflammatory effects of TAB3 were then explored both in vitro and in vivo. Adeno-associated virus 9 (AAV9)-mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and ischemia/reperfusion-induced renal injury and inflammation than S-adenosyl-l-homocysteine, a previously identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modifications of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both genetic and pharmacological inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI.

DOI: https://doi.org/10.1126/scitranslmed.abk2709
Front Cell Dev Biol. 2022 ;10 853596

SLC2A1 is a Diagnostic Biomarker Involved in Immune Infiltration of Colorectal Cancer and Associated With m6A Modification and ceRNA.

Xu-Sheng Liu, Jian-Wei Yang, Jing Zeng, Xue-Qin Chen, Yan Gao, Xue-Yan Kui, Xiao-Yu Liu, Yu Zhang, Yao-Hua Zhang, Zhi-Jun Pei.

  Background: Overexpression of solute carrier family 2 member 1 (SLC2A1) promotes glycolysis and proliferation and migration of various tumors. However, there are few comprehensive studies on SLC2A1 in colorectal cancer (CRC). Methods: Oncomine, The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases were used to analyze the expression of SLC2A1 in pan-cancer and CRC and analyzed the correlation between SLC2A1 expression and clinical characteristics of TCGA CRC samples. The expression level of SLC2A1 in CRC was certified by cell experiments and immunohistochemical staining analysis. The Genome Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses of SLC2A1 relative genes were completed by bioinformatics analysis. The correlation between SLC2A1 expression level and CRC immune infiltration cell was analyzed by Tumor IMmune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), and TCGA database. The correlation between SLC2A1 expression level and ferroptosis and m6A modification of CRC was analyzed by utilizing TCGA and GEO cohort. Finally, the possible competing endogenous RNA (ceRNA) networks involved in SLC2A1 in CRC are predicted and constructed through various databases. Results: SLC2A1 is highly expressed not only in CRC but also in many other tumors. ROC curve indicated that SLC2A1 had high predictive accuracy for the outcomes of tumor. The SLC2A1 expression in CRC was closely correlated with tumor stage and progression free interval (PFI). GO, KEGG, and GSEA analysis indicated that SLC2A1 relative genes were involved in multiple biological functions. The analysis of TIMER, GEPIA, and TCGA database indicated that the SLC2A1 mRNA expression was mainly positively associated with neutrophils. By the analysis of the TCGA and GEO cohort, we identified that the expression of SLC2A1 is closely associated to an m6A modification relative gene Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3) and a ferroptosis relative gene Glutathione Peroxidase 4 (GPX4). Conclusion: SLC2A1 can be used as a biomarker of CRC, which is associated to immune infiltration, m6A modification, ferroptosis, and ceRNA regulatory network of CRC.

Keywords:  SLC2A1; ceRNA; colorectal cancer; immune infiltration; m6A modification

DOI:  https://doi.org/10.3389/fcell.2022.853596