bims-rimeca 2023-06-11 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023‒06‒11
twenty-six papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

PRMT1 methylates METTL14 to modulate its oncogenic function.
METTL14 suppresses cancer stem cell phenotype of colorectal cancer via regulating of β-catenin/NANOG.
The emerging roles and mechanism of N6-methyladenosine (m6A) modifications in urologic tumours progression.
Role of m6A modification in immune microenvironment of digestive system tumors.
Increased METTL3 expression and m6A RNA methylation may contribute to the development of dry eye in primary Sjögren's syndrome.
Mettl3 Mediated m6A Methylation Involved in Epithelial-Mesenchymal Transition by Targeting SOCS3/STAT3/SNAI1 in Cigarette Smoking-Induced COPD.
Regulation of RNA methylation by therapy treatment, promotes tumor survival.
High-throughput Sequencing Reveals N6-methyladenosine-modified LncRNAs as Potential Biomarkers in Mice with Liver Fibrosis.
METTL3-mediated m6A modification of IGFBP7-OT promotes osteoarthritis progression by regulating the DNMT1/DNMT3a-IGFBP7 axis.
Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential.
Profile of N6-methyladenosine of Pb-exposed neurons presents epitranscriptomic alterations in PI3K-AKT pathway-associated genes.
N6-methyladenosine (m6A) Modification in Preeclampsia.
Linc00662 m6A promotes the progression and metastasis of pancreatic cancer by activating focal adhesion through the GTF2B-ITGA1-FAK pathway.
The Landscape of m6A Regulators in Multiple Brain Regions of Alzheimer's Disease.
Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice.
H19 recruited m6A reader YTHDF1 to promote SCARB1 translation and facilitate angiogenesis in gastric cancer.
Mettl14-mediated m6A modification ensures the cell-cycle progression of late-born retinal progenitor cells.
The plant cytosolic m6A RNA methylome stabilizes photosynthesis in the cold.
METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling.
AHR-mediated m6A RNA methylation contributes to PM2.5-induced cardiac malformations in zebrafish larvae.
Inhibition of DNA and RNA methylation disturbs root development of moso bamboo.
RNA N6-methyladenosine profiling reveals differentially methylated genes associated with intramuscular fat metabolism during breast muscle development in chicken.
Tumor-associated macrophages promote cisplatin resistance in ovarian cancer cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis.
Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease.
LINC00641 impeded the malignant biological behaviors of papillary thyroid carcinoma cells via interacting with IGF2BP1 to reduce GLI1 mRNA stability.
N7-methylguanosine modification: from regulatory roles to therapeutic implications in cancer.

Neoplasia. 2023 Jun 01. pii: S1476-5586(23)00037-4. [Epub ahead of print]42 100912

PRMT1 methylates METTL14 to modulate its oncogenic function.

Jingchao Wang, Zhen Wang, Hiroyuki Inuzuka, Wenyi Wei, Jing Liu.

  N6-methyladenosine (m6A), the most abundant mRNA modification in mammalian cells, is responsible for mRNA stability and alternative splicing. The METTL3-METTL14-WTAP complex is the only methyltransferase for the m6A modification. Thus, regulation of its enzymatic activity is critical for the homeostasis of mRNA m6A levels in cells. However, relatively little is known about the upstream regulation of the METTL3-METTL14-WTAP complex, especially at the post-translational modification level. The C-terminal RGG repeats of METTL14 are critical for RNA binding. Therefore, modifications on these residues may play a regulatory role in its function. Arginine methylation is a post-translational modification catalyzed by protein arginine methyltransferases (PRMTs), among which PRMT1 preferentially methylates protein substrates with an arginine/glycine-rich motif. In addition, PRMT1 functions as a key regulator of mRNA alternative splicing, which is associated with m6A modification. To this end, we report that PRMT1 promotes the asymmetric methylation of two major arginine residues at the C-terminus of METTL14, and the reader protein SPF30 recognizes this modification. Functionally, PRMT1-mediated arginine methylation on METTL14 is likely essential for its function in catalyzing the m6A modification. Moreover, arginine methylation of METTL14 promotes cell proliferation that is antagonized by the PRMT1 inhibitor MS023. These results indicate that PRMT1 likely regulates m6A modification and promotes tumorigenesis through arginine methylation at the C-terminus of METTL14.

Keywords:  Arginine methylation; METTL14; N6-methyladenosine (m6A); PRMT1

DOI:  https://doi.org/10.1016/j.neo.2023.100912
J Cancer. 2023 ;14(8): 1407-1416

METTL14 suppresses cancer stem cell phenotype of colorectal cancer via regulating of β-catenin/NANOG.

Chun-Lei Sun, Jiong Chen, Zhi-Wei Xing, Gong-Shai Tao.

  Cancer stem cell (CSC) characteristic contributes to tumor malignancy and progression. The role of N6-methyladenosine (m6A) modification in CSC characteristic is largely unknown. In this study, we found that m6A methyltransferase METTL14 was downregulated in colorectal cancer (CRC) and negatively correlated with the poor prognosis of CRC patients. Overexpression of METTL14 inhibited CSC characteristic, while knockdown of METTL14 promoted this characteristic. Through screening, NANOG was identified as the downstream of METTL14. Mechanically, we demonstrated that METTL14 inhibited cancer stem cell characteristic by regulating β-catenin. Collectively, our findings suggested that METTL16/β-catenin /NANOG axis might be promising therapeutic targets for CRC.

Keywords:  Colorectal cancer; METTL14; NANOG; cancer stem cell phenotype; m6A; β-catenin

DOI:  https://doi.org/10.7150/jca.82158
Front Pharmacol. 2023 ;14 1192495

The emerging roles and mechanism of N6-methyladenosine (m6A) modifications in urologic tumours progression.

Wenhao Zhu, Renshan Zhao, Xiaomin Guan, Xu Wang.

  Prostate cancer (PCa), bladder cancer (BC), and renal cell cancer (RCC) are the most common urologic tumours in males. N6-methyladenosine (m6A), adenosine N6 methylation, is the most prevalent RNA modification in mammals. Increasing evidence suggests that m6A plays a crucial role in cancer development. In this review, we comprehensively analyzed the influence of m6A methylation on Prostate cancer, bladder cancer, and renal cell cancer and the relationship between the expression of relevant regulatory factors and their development and occurrence, which provides new insights and approaches for the early clinical diagnosis and targeted therapy of urologic malignancies.

Keywords:  N6-methyladenosine; coding RNAs; epitranscriptome; non-coding RNAs; posttranscriptional modification; urologic tumours

DOI:  https://doi.org/10.3389/fphar.2023.1192495
Biomed Pharmacother. 2023 May 31. pii: S0753-3322(23)00743-6. [Epub ahead of print]164 114953

Role of m6A modification in immune microenvironment of digestive system tumors.

Chao Li, Mengqi Zhu, Jiajia Wang, Hengshuang Wu, Yameng Liu, Di Huang.

  Digestive system tumors are huge health problem worldwide, largely attributable to poor dietary choices. The role of RNA modifications in cancer development is an emerging field of research. RNA modifications are associated with the growth and development of various immune cells, which, in turn, regulate the immune response. The majority of RNA modifications are methylation modifications, and the most common type is the N6-methyladenosine (m6A) modification. Here, we reviewed the molecular mechanism of m6A in the immune cells and the role of m6A in the digestive system tumors. However, further studies are required to better understand the role of RNA methylation in human cancers for designing diagnostic and treatment strategies and predicting the prognosis of patients.

Keywords:  Digestive system tumors; Function; Immune microenvironment; N6-methyladenosine (m6A); Prognosis

DOI:  https://doi.org/10.1016/j.biopha.2023.114953
BMC Ophthalmol. 2023 Jun 05. 23(1): 252

Increased METTL3 expression and m6A RNA methylation may contribute to the development of dry eye in primary Sjögren's syndrome.

Jun Ma, Xiaotang Wang, Xue Yang, Xi Wang, Tongshan Tan, Hongping Fang, Yu Zhong, Qi Zhang.

  BACKGROUND: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder defined by xerostomia and keratoconjunctivitis sicca, and its etiology remains unknown. N6-methyladenosine (m6A) is the predominant posttranscriptional modification in eukaryotic mRNAs and is dynamically regulated by m6A regulators. Dysregulation of m6A modification is closely associated with several autoimmune disorders, but the role of m6A modification in pSS remains unknown. This study investigated the potential role of m6A and m6A-related regulators in pSS patients with dry eye.METHODS: This cross-sectional study included forty-eight pSS patients with dry eye and forty healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) were isolated, and the level of m6A in total RNA was measured. The expression of m6A regulators was determined utilizing real-time PCR and western blotting. The serological indicators detected included autoantibodies, immunoglobulins (Igs), complement factors (Cs), and inflammatory indicators. Dry eye symptoms and signs were measured, including the ocular surface disease index, Schirmer's test (ST), corneal fluorescein staining score (CFS), and tear break-up time. Spearman's correlation coefficient was employed to assess the associations of m6A and m6A-related regulator expression with clinical characteristics.
RESULTS: The expression level of m6A was markedly increased in the PBMCs of pSS patients with dry eye compared to HCs (P value<0.001). The relative mRNA and protein expression levels of the m6A regulators methyltransferase-like 3 (METTL3) and YT521-B homology domains 1 were markedly elevated in pSS patients with dry eye (both P value<0.01). The m6A RNA level was found to be positively related to METTL3 expression in pSS patients (r = 0.793, P value<0.001). Both the m6A RNA level and METTL3 mRNA expression correlated with the anti-SSB antibody, IgG, ST, and CFS (all P values < 0.05). The m6A RNA level was associated with C4 (r = -0.432, P value = 0.002), while METTL3 mRNA expression was associated with C3 (r = -0.313, P value = 0.030).
CONCLUSIONS: Our work revealed that the upregulation of m6A and METTL3 was associated with the performance of serological indicators and dry eye signs in pSS patients with dry eye. METTL3 may contribute to the pathogenesis of dry eye related to pSS.

Keywords:  Dry eye; METTL3; N6-methyladenosine; Primary Sjögren’s syndrome

DOI:  https://doi.org/10.1186/s12886-023-02988-0
Int J Chron Obstruct Pulmon Dis. 2023 ;18 1007-1017

Mettl3 Mediated m6A Methylation Involved in Epithelial-Mesenchymal Transition by Targeting SOCS3/STAT3/SNAI1 in Cigarette Smoking-Induced COPD.

Yaping Zhang, Lixing Wang, Furong Yan, Meili Yang, Hongzhi Gao, Yiming Zeng.

  Purpose: Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation modification was discovered to play an important role in various diseases. Nevertheless, the regulatory role of m6A methylation has not yet been investigated in cigarette smoking-induced COPD. The study aims to explore the regulatory role of m6A methylation in cigarette smoking-induced COPD.Patients and Methods: In this study, two Gene Expression Omnibus (GEO) datasets were first utilized to analyze the expression profiles of m6A RNA methylation regulators in COPD. We then established a cell model of COPD by exposing human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) in vitro and detected the expression of m6A writer Mettl3 and EMT phenotype markers. RNA interference, cycloleucine, RT-qPCR, western blot, MeRIP-sequencing, and cell migration assay were performed to investigate the potential effect of Mettl3 on the EMT process in CSE-induced HBECs.
Results: Our results showed that Mettl3 expression was significantly elevated in cigarette smoking-induced COPD patients and in a cellular model of COPD. Furthermore, Mettl3 silence and cycloleucine treatment inhibited the EMT process of HBECs caused by CSE. Mechanically, Mettl3 silence weakens the m6A methylation of SOCS3 mRNA to enhance the protein expression of SOCS3, inhibiting CSE-induced SOCS3/STAT3/SNAI1 signaling and EMT processes in HBECs.
Conclusion: Our study inferred that Mettl3-mediated m6A RNA methylation modification modulates CSE-induced EMT by targeting SOCS3 mRNA and ultimately serves as a crucial regulator in the emergence of COPD. This conclusion reinforces the regulatory role of m6A methylation in COPD.

Keywords:  COPD; MeRIP–sequencing; cycloleucine; inflammation

DOI:  https://doi.org/10.2147/COPD.S398289
bioRxiv. 2023 May 20. pii: 2023.05.19.540602. [Epub ahead of print]

Regulation of RNA methylation by therapy treatment, promotes tumor survival.

Syed Ia Bukhari, Samuel S Truesdell, Chandreyee Datta, Pritha Choudhury, Keith Q Wu, Jitendra Shrestha, Ruby Maharjan, Ethan Plotsker, Ramzi Elased, Sadia Laisa, Vijeta Bhambhani, Yue Lin, Johannes Kreuzer, Robert Morris, Siang-Boon Koh, Leif W Ellisen, Wilhelm Haas, Amy Ly, Shobha Vasudevan.

Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival.One sentence summary: m6A enzyme translation upon therapy stress, promotes tumor survival.

DOI: https://doi.org/10.1101/2023.05.19.540602
Curr Gene Ther. 2023 Jun 06.

High-throughput Sequencing Reveals N6-methyladenosine-modified LncRNAs as Potential Biomarkers in Mice with Liver Fibrosis.

Furong Wu, Shengyu Zhang, Chang Fan, Shaopeng Huang, Hui Jiang, Jiafu Zhang.

  BACKGROUND: N6-methyladenosine (m6A) is the most frequent internal modification in eukaryotic RNA. Long noncoding RNAs (lncRNAs) are a new type of noncoding regulatory molecule with multiple cellular functions. Both are closely related to the occurrence and development of liver fibrosis (LF). However, the role of m6A-methylated lncRNAs in the progression of LF remains largely unknown.METHODS: In this study, HE and Masson staining were used to observe pathological changes in the liver, m6A-modified RNA immunoprecipitation sequencing (m6A-seq) was performed to systematically evaluate the m6A modification level of lncRNAs in LF mice, meRIP-qPCR and RT-qPCR were used to detect the m6A methylation level and RNA expression level of the target lncRNAs.
RESULTS: A total of 415 m6A peaks were detected in 313 lncRNAs in liver fibrosis tissues. There were 98 significantly different m6A peaks in LF, which were located on 84 lncRNAs, of which 45.2% of the lncRNA length was between 200-400 bp. At the same time, the first three chromosomes of these methylated lncRNAs were chromosomes 7, 5 and 1. RNA sequencing identified 154 differentially expressed lncRNAs in LF. The joint analysis of m6A-seq and RNA-seq found that there were three lncRNAs with significant changes in m6A methylation and RNA expression levels: lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586. Subsequently, the verification results showed that the m6A methylation levels of lncRNA H19 and lncRNA Gm17586 were significantly increased, while that of lncRNA Gm16023 was significantly decreased, and the RNA expression of three lncRNAs was significantly decreased. Through the establishment of a lncRNA-miRNA-mRNA regulatory network, the possible regulatory relationships of lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586 in LF were revealed.
CONCLUSION: This study revealed the unique m6A methylation pattern of lncRNAs in LF mice, suggesting that the m6A methylation modification of lncRNAs is related to the occurrence and development of LF.

Keywords:  N6-methyladenosine; high-throughput sequencing; liver fibrosis; lncRNA; meRIP-qPCR; regulatory network

DOI:  https://doi.org/10.2174/1566523223666230606151013
Cell Rep. 2023 Jun 02. pii: S2211-1247(23)00600-9. [Epub ahead of print]42(6): 112589

METTL3-mediated m6A modification of IGFBP7-OT promotes osteoarthritis progression by regulating the DNMT1/DNMT3a-IGFBP7 axis.

Yuting Tang, Fangling Hong, Siyang Ding, Jiashu Yang, Ming Zhang, Yunfei Ma, Que Zheng, Dawei Yang, Yucui Jin, Changyan Ma.

  Osteoarthritis (OA) is the most common degenerative disorder, affecting approximately half of the elderly population. In this study, we find that the expressions of long noncoding RNA (lncRNA) IGFBP7-OT and its maternal gene, IGFBP7, are upregulated and positively correlated in osteoarthritic cartilage. Overexpression of IGFBP7-OT significantly inhibits chondrocyte viability, promotes chondrocyte apoptosis, and reduces extracellular matrix components, whereas IGFBP7-OT knockdown has the opposite effects. IGFBP7-OT overexpression promotes cartilage degeneration and markedly aggravates the monosodium iodoacetate-induced OA phenotype in vivo. Further mechanistic research reveals that IGFBP7-OT promotes OA progression by upregulating IGFBP7 expression. Specifically, IGFBP7-OT suppresses the occupancy of DNMT1 and DNMT3a on the IGFBP7 promoter, thereby inhibiting methylation of the IGFBP7 promoter. The upregulation of IGFBP7-OT in OA is partially controlled by METTL3-mediated N6-methyladenosine (m6A) modification. Collectively, our findings reveal that m6A modification of IGFBP7-OT promotes OA progression by regulating the DNMT1/DNMT3a-IGFBP7 axis and provide a potential therapeutical target for OA treatment.

Keywords:  CP: Immunology; DNA methylation; IGFBP7; IGFBP7-OT; METTL3; osteoarthritis

DOI:  https://doi.org/10.1016/j.celrep.2023.112589
Biomark Res. 2023 Jun 06. 11(1): 62

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential.

Tian-Yu Zhu, Lian-Lian Hong, Zhi-Qiang Ling.

  N6-methyladenosine (m6A) is the most prevalent and well-characterized internal chemical modification in eukaryotic RNA, influencing gene expression and phenotypic changes by controlling RNA fate. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) preferentially function as m6A effector proteins, promoting stability and translation of m6A-modified RNAs. IGF2BPs, particularly IGF2BP1 and IGF2BP3, are widely recognized as oncofetal proteins predominantly expressed in cancer rather than normal tissues, playing a critical role in tumor initiation and progression. Consequently, IGF2BPs hold potential for clinical applications and serve as a good choice for targeted treatment strategies. In this review, we discuss the functions and mechanisms of IGF2BPs as m6A readers and explore the therapeutic potential of targeting IGF2BPs in human cancer.

Keywords:  Cancer; IGF2BPs; Therapeutic target; m6A

DOI:  https://doi.org/10.1186/s40364-023-00499-0
Food Chem Toxicol. 2023 Jun 01. pii: S0278-6915(23)00223-5. [Epub ahead of print] 113821

Profile of N6-methyladenosine of Pb-exposed neurons presents epitranscriptomic alterations in PI3K-AKT pathway-associated genes.

Shu Ai, Danyang Li, Xiaozhen Gu, Yi Xu, Yi Wang, Hui-Li Wang, Xiang-Tao Chen.

  Lead (Pb) is a pervasive heavy metal with multi-organ toxicity. However, the molecular mechanisms of Pb-induced neurotoxicity are not fully understood. The dynamics of N6-methylademine (m6A) is an emerging regulatory mechanism for gene expression, which is closely related to nervous system diseases. To elucidate the association between m6A modification and Pb-mediated neurotoxicity, primary hippocampal neurons exposed to 5 μM Pb for 48 h were used as the paradigm neurotoxic model in this study. According to the results, Pb exposure reprogrammed the transcription spectrum. Simultaneously, Pb exposure remodeled the transcriptome-wide distribution of m6A while disrupting the overall level of m6A in cellular transcripts. United analysis of MeRIP-Seq and RNA-Seq was applied to further identify the core genes whose expression levels are regulated by m6A in the process of lead-induced nerve injury. GO and KEGG analysis unveiled that the modified transcripts were overrepresented by the PI3K-AKT pathway. Mechanically, we elucidated the regulatory role of the methyltransferase like3 (METTL3) in the process of lead-induced neurotoxicity and the downregulation of the PI3K-AKT pathway. In conclusion, our novel findings shed new light on the functional roles of m6A modification in the expressional alternations of downstream transcripts caused by lead, providing an innovative molecular basis to explain Pb neurotoxicity.

Keywords:  Epitranscriptome; Lead; N6-methyladenosine (m6A); Neurotoxicity; PI3K-AKT Pathway

DOI:  https://doi.org/10.1016/j.fct.2023.113821
Reprod Sci. 2023 Jun 07.

N6-methyladenosine (m6A) Modification in Preeclampsia.

Tingting Zhang, Ziyan Jiang, Nana Yang, Zhiping Ge, Qing Zuo, Shiyun Huang, Lizhou Sun.

  Recently, epitranscriptional modification of N6-methyladenosine (m6A) has received growing attention in the research on the pathogenesis of preeclampsia. Advances in m6A sequencing have revealed the molecular mechanism and importance of m6A modification. In addition, epitranscriptional modification of m6A is closely related to the metabolic processes of placental tissues and cells in preeclampsia. This article reviews the composition, mode of action, and bioinformatics analysis of m6A modification-related proteins, and their biological function in the progression of preeclampsia. The relationship between m6A modification and preeclampsia risk factors, such as diabetes, cardiovascular disease, obesity, and psychological stress, is summarized to provide new ideas for studying PE-targeting molecules.

Keywords:  N6-methyladenosine; Placenta; Preeclampsia; Trophoblast

DOI:  https://doi.org/10.1007/s43032-023-01250-8
Am J Cancer Res. 2023 ;13(5): 1718-1743

Linc00662 m6A promotes the progression and metastasis of pancreatic cancer by activating focal adhesion through the GTF2B-ITGA1-FAK pathway.

Shuo Zhang, Tiantian Lai, Xiaowen Su, Yong Zhang, Junjing Zhou, Changyong Zhao, Minfeng Liu, Wuqiang Chen, Shuming Xiong, Yue Tao, Youzhao He, Hao Hu.

Recurrence and metastasis are major factors associated with the poor prognosis of pancreatic cancer (PC). Previous studies have indicated that METTL3-mediated N6-methyladenosine (m6A) modification is closely associated with PC progression and prognosis. However, its underlying regulatory mechanisms remain unclear. In this study, we found that METTL3 was upregulated in PC tissues and cells and was associated with malignant tumor progression and poor progression-free survival in PC. Linc00662 was screened as a m6A-enriched RNA that promoted tumor growth and metastasis in PC cells and mouse models and was associated with poor clinical prognosis. Four m6A motifs were identified in Linc00662, which maintained the stability of Linc00662 in an IGF2BP3-coupled manner and were closely associated with the pro-tumor properties of Linc00662 in vitro and in vivo. ITGA1 was identified as a downstream gene regulated by Linc00662. Linc00662 recruites GTF2B to activate the transcription of ITGA1 in a m6A-dependent manner and initiates the formation of focal adhesions through the ITGA1-FAK-Erk pathway, thereby promoting malignant behavior in PC cells. The FAK inhibitor-Y15 obviously repressed tumor progression in Linc00662-overexpressing PC cells in vitro and in vivo. This study proposes a novel regulatory mechanism of Linc00662 in oncogene activation in PC and indicates that Linc00662 and its downstream genes are potential targets for PC therapy.

Keywords: FAK; ITGA1; Linc00662; N6-methyladenosine; Pancreatic cancer; focal adhesion
Mol Neurobiol. 2023 Jun 05.

The Landscape of m6A Regulators in Multiple Brain Regions of Alzheimer's Disease.

ZiJie Liu, Qing Xia, Xue Zhao, FeiFei Zheng, JiaYing Xiao, FangLiang Ge, DaYong Wang, Xu Gao.

  Alzheimer's disease research has been conducted for many years, yet no effective cure methods have been found. N6-methyladenosine (m6A) RNA methylation, an essential post-transcriptional regulation mechanism, has been discovered to affect essential neurobiological processes, such as brain cell development and aging, which are closely related to neurodegenerative diseases such as Alzheimer's disease. The relationship between Alzheimer's disease and the m6A mechanism still needs further investigation. Our work evaluated the alteration profile of m6A regulators and their influences on Alzheimer's disease in 4 brain regions: the postcentral gyrus, superior frontal gyrus, hippocampus, and entorhinal cortex. We found that the expression levels of the m6A regulators FTO, ELAVL1, and YTHDF2 were altered in Alzheimer's disease and were related to pathological development and cognitive levels. We also assessed AD-related biological processes influenced by m6A regulators via GSEA and GSVA method. Biological Processes Gene Ontology terms including memory, cognition, and synapse-signaling were found to potentially be affected by m6A regulators in AD. We also found different m6A modification patterns in AD samples among different brain regions, mainly due to differences in m6A readers. Finally, we further evaluated the importance of AD-related regulators based on the WGCNA method, assessed their potential targets based on correlation relationships, and constructed diagnostic models in 3 of all 4 regions using hub regulators, including FTO, YTHDC1, YTHDC2, etc., and their potential targets. This work aims to provide a reference for the follow-up study of m6A and Alzheimer's disease.

Keywords:  Alzheimer’s disease; Brain regions; FTO; YTHDF2; m6A

DOI:  https://doi.org/10.1007/s12035-023-03409-5
Neural Regen Res. 2023 Nov;18(11): 2545-2552

Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice.

Fanning Zeng, Jun Cao, Zexuan Hong, Yitian Lu, Zaisheng Qin, Tao Tao.

  Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuropathic pain. N6-methyladenosine (m6A) is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases. However, the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown. In this study, we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve. High-throughput methylated RNA immunoprecipitation sequencing results showed that after spared nerve injury, there were 55 m6A methylated and differentially expressed genes in the spinal cord. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury. Over time, the differential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell proliferation." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance. Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes, such as "very-low-density lipoprotein particle clearance," "negative regulation of cholesterol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling. We speculate that m6A reader enzymes also have an important role in neuropathic pain. These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at different stages after injury.

Keywords:  MeRIP-Seq; Nlrp1b; RNA methylation; Ythdf2; epigenetic; m6A; m6A reader; neuropathic pain; spared nerve injury

DOI:  https://doi.org/10.4103/1673-5374.371374
Chin Med J (Engl). 2023 Jun 05.

H19 recruited m6A reader YTHDF1 to promote SCARB1 translation and facilitate angiogenesis in gastric cancer.

Rumeng Bai, Miaomiao Sun, Yuanyuan Chen, Shuaishuai Zhuo, Guoxin Song, Tianjun Wang, Zhihong Zhang.

BACKGROUND: Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism.METHODS: Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo. The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay.
RESULTS: In this study, we found that hypoxia-induced factor (HIF-1α) could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N6-methyladenosine (m6A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m6A site on the 3'-untransated regions (3'-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells.
CONCLUSION: HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.

DOI: https://doi.org/10.1097/CM9.0000000000002722
Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00607-1. [Epub ahead of print]42(6): 112596

Mettl14-mediated m6A modification ensures the cell-cycle progression of late-born retinal progenitor cells.

Liang Li, Yue Sun, Alexander E Davis, Sahil H Shah, Lobna K Hamed, Man-Ru Wu, Cheng-Hui Lin, Jun B Ding, Sui Wang.

  Neural progenitor cells lengthen their cell cycle to prime themselves for differentiation as development proceeds. It is currently not clear how they counter this lengthening and avoid being halted in the cell cycle. We show that N6-methyladenosine (m6A) methylation of cell-cycle-related mRNAs ensures the proper cell-cycle progression of late-born retinal progenitor cells (RPCs), which are born toward the end of retinogenesis and have long cell-cycle length. Conditional deletion of Mettl14, which is required for depositing m6A, led to delayed cell-cycle exit of late-born RPCs but has no effect on retinal development prior to birth. m6A sequencing and single-cell transcriptomics revealed that mRNAs involved in elongating the cell cycle were highly enriched for m6A, which could target them for degradation and guarantee proper cell-cycle progression. In addition, we identified Zfp292 as a target of m6A and potent inhibitor of RPC cell-cycle progression.

Keywords:  CP: Developmental biology; CP: Neuroscience; Epitranscriptomic regulation; Mettl14; Zfp292; cell cycle; m(6)A mRNA methylation; retinal development; retinal progenitor cells (RPCs)

DOI:  https://doi.org/10.1016/j.celrep.2023.112596
Plant Commun. 2023 Jun 07. pii: S2590-3462(23)00151-7. [Epub ahead of print] 100634

The plant cytosolic m6A RNA methylome stabilizes photosynthesis in the cold.

Alexandre Magno Vicente, Nikolay Manavski, Paul Torben Rohn, Lisa-Marie Schmid, Antoni Garcia-Molina, Dario Leister, Charlotte Seydel, Leo Bellin, Torsten Möhlmann, Gregor Ammann, Stefanie Kaiser, Jörg Meurer.

  The sessile lifestyle of plants requires an immediate response to environmental stressors that affect photosynthesis, growth, and crop yield. Here, we showed that three abiotic perturbations - heat, cold, and high light - triggered considerable changes in the expression signature of 42 epitranscriptomic factors (writers, erasers, and readers) with putative chloroplast-associated functions that formed clusters of commonly expressed genes. The expression changes under all conditions were reversible upon de-acclimation, identifying epitranscriptomic players as modulators in acclimation processes. Chloroplast dysfunctions, particularly those induced by the oxidative stress-inducing norflurazon in a largely GENOME UNCOUPLED (GUN)-independent manner, triggered retrograde signals to remodel chloroplast-associated epitranscriptomic expression patterns. N6-methyladenosine (m6A) is known as the most prevalent RNA modification and impacts numerous developmental and physiological functions in living organisms. During cold treatment, expression of components of the primary nuclear m6A methyltransferase complex was upregulated, accompanied by a significant increase in cellular m6A mRNA marks. In the cold, the presence of FIP37, a core component of the writer complex, plays an important role in the positive regulation of thylakoid structure, photosynthetic functions, and accumulation of photosystem (PS)I, Cytb6f complex, cyclic electron transport (CET) proteins, and Curvature Thylakoid1 (CurT1) but not that of PSII components and the chloroplast ATP synthase. Downregulation of FIP37 affects abundance, polysomal loading, and translation of cytosolic transcripts related to photosynthesis in the cold suggesting m6A-dependent translational regulation of chloroplast functions. In summary, we identified multifaceted roles of the cellular m6A RNA methylome in coping with cold predominantly associated with chloroplasts to stabilize photosynthesis.

Keywords:  Arabidopsis thaliana; RNA methylation; chloroplast; cold acclimation; m(6)A; photosynthesis; stress response

DOI:  https://doi.org/10.1016/j.xplc.2023.100634
Cell Death Dis. 2023 Jun 03. 14(6): 349

METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling.

Shuo Wan, Yadong Sun, Jinbao Zong, Wanqing Meng, Jiacong Yan, Kexin Chen, Sanfeng Wang, Daji Guo, Zhiqiang Xiao, Qinghua Zhou, Zhinan Yin, Meixiang Yang.

Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m6A modification in infertility remains unknown. Here we report that METTL3-dependent m6A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation of METTL3 expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion of Mettl3 in female reproductive tract by using a Pgr-Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m6A-seq analysis of the uterus identifies the 3'UTR of several estrogen-responsive genes with METTL3-dependent m6A modification, like Elf3 and Celsr2, whose mRNAs become more stable upon Mettl3 depletion. However, the decreased expression levels of PR and its target genes, including Myc, in the endometrium of Mettl3 cKO mice indicate a deficiency in progesterone responsiveness. In vitro, Myc overexpression could partially compensate for uterine decidualization failure caused by Mettl3 deficiency. Collectively, this study reveals the role of METTL3-dependent m6A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.

DOI: https://doi.org/10.1038/s41419-023-05866-1
J Hazard Mater. 2023 Jun 02. pii: S0304-3894(23)01032-4. [Epub ahead of print]457 131749

AHR-mediated m6A RNA methylation contributes to PM2.5-induced cardiac malformations in zebrafish larvae.

Cheng Ji, Yizhou Tao, Xiaoxiao Li, Jin Wang, Jin Chen, Stanley Aniagu, Yan Jiang, Tao Chen.

  A growing body of evidence indicates that ambient fine particle matter (PM2.5) exposure inhibits heart development, but the underlying mechanisms remain elusive. We hypothesized that m6A RNA methylation plays an important role in the cardiac developmental toxicity of PM2.5. In this study, we demonstrated that extractable organic matter (EOM) from PM2.5 significantly decreased global m6A RNA methylation levels in the heart of zebrafish larvae, which were restored by the methyl donor, betaine. Betaine also attenuated EOM-induced ROS overgeneration, mitochondrial damage, apoptosis and heart defects. Furthermore, we found that the aryl hydrocarbon receptor (AHR), which was activated by EOM, directly repressed the transcription of methyltransferases mettl14 and mettl3. EOM also induced genome-wide m6A RNA methylation changes, which led us to focus more on the aberrant m6A methylation changes that were subsequently alleviated by the AHR inhibitor, CH223191. In addition, we found that the expression levels of traf4a and bbc3, two apoptosis related genes, were upregulated by EOM but restored to control levels by the forced expression of mettl14. Moreover, knockdown of either traf4a or bbc3 attenuated EOM-induced ROS overproduction and apoptosis. In conclusion, our results indicate that PM2.5 induces m6A RNA methylation changes via AHR-mediated mettl14 downregulation, which upregulates traf4a and bbc3, leading to apoptosis and cardiac malformations.

Keywords:  AHR; Heart development; M(6)A RNA methylation; PM(2.5); Zebrafish

DOI:  https://doi.org/10.1016/j.jhazmat.2023.131749
Tree Physiol. 2023 Jun 09. pii: tpad074. [Epub ahead of print]

Inhibition of DNA and RNA methylation disturbs root development of moso bamboo.

Yuxiang Liufu, Feihu Xi, Lin Wu, Zeyu Zhang, Huihui Wang, Huiyuan Wang, Jun Zhang, Baijie Wang, Wenjing Kou, Jian Gao, Liangzhen Zhao, Hangxiao Zhang, Lianfeng Gu.

  DNA methylation (5mC) and N6-methyladenosine (m6A) are two important epigenetics regulation, which presents profound impact on plant growth development. Phyllostachys edulis (P. edulis) is one of the fastest spreading plants due to its well-developed root system. However, the association between 5mC and m6A were seldom reported in P. edulis. Especially, the connection between m6A and several post-transcriptional regulations remains uncharacterized in P. edulis. Here, our morphological and electron microscope observation shown phenotype of increased lateral root under RNA methylation inhibitor (DZnepA) and DNA methylation inhibitor (5-azaC) treatment. RNA epitranscriptome based on Nanopore direct RNA sequencing (DRS) revealed that DZnepA treatment exhibits significantly decreased m6A level in 3' UTR, which was accompanied by increased gene expression, full-length ratio, higher proximal poly(A) site usage, and shorter poly(A) tail length, respectively. DNA methylation levels of CG and CHG were reduced in both CDS and transposable element (TE) upon 5-azaC treatment. Cell wall synthesis was impaired under methylation inhibition. Especially, differentially expressed genes (DEGs) presented high percentage of overlap between DZnepA and 5-azaC treatment, which suggested a potential correlation between two methylations. This study provides preliminary information for a better understanding of the link between m6A and 5mC in root development of moso bamboo.

Keywords:  DNA methylation; N6-methyladenosine; Phyllostachys edulis; alternative polyadenylation; long non-coding RNA; poly(A) tail length

DOI:  https://doi.org/10.1093/treephys/tpad074
Poult Sci. 2023 May 19. pii: S0032-5791(23)00312-7. [Epub ahead of print]102(8): 102793

RNA N6-methyladenosine profiling reveals differentially methylated genes associated with intramuscular fat metabolism during breast muscle development in chicken.

Baojun Yu, Jiamin Liu, Zhengyun Cai, Haorui Wang, Xiaofang Feng, Tong Zhang, Ruoshuang Ma, Yaling Gu, Juan Zhang.

  Intramuscular fat (IMF) is an important indicator for determining meat quality, and IMF deposition during muscle development is regulated by a complex molecular network involving multiple genes. The N6-methyladenosine (m6A) modification of mRNA plays an important regulatory role in muscle adipogenesis. However, the distribution of m6A and its role in IMF metabolism in poultry has not been reported. In the present study, a transcriptome-wide m6A profile was constructed using methylated RNA immunoprecipitation sequence (MeRIP-seq) and RNA sequence (RNA-seq) to explore the potential mechanism of regulating IMF deposition in the breast muscle based on the comparative analysis of IMF differences in the breast muscles of 42 (group G), 126 (group S), and 180-days old (group M) Jingyuan chickens. The findings revealed that the IMF content in the breast muscle increased significantly with the increase in the growth days of the Jingyuan chickens (P < 0.05). The m6A peak in the breast muscles of the 3 groups was highly enriched in the coding sequence (CDS) and 3' untranslated regions (3' UTR), which corresponded to the consensus motif RRACH. Moreover, we identified 129, 103, and 162 differentially methylated genes (DMGs) in the breast muscle samples of the G, S, and M groups, respectively. Functional enrichment analyses revealed that DMGs are involved in many physiological activities of muscle fat anabolism. The m6A-induced ferroptosis pathway was identified in breast muscle tissue as a new target for regulating IMF metabolism. In addition, association analysis demonstrated that LMOD2 and its multiple m6A negatively regulated DMGs are potential regulators of IMF differential deposition in muscle. The findings of the present study provide a solid foundation for further investigation into the potential role of m6A modification in regulating chicken fat metabolism.

Keywords:  Jingyuan chicken; MeRIP-seq; N(6)-methyladenosine; intramuscular fat; transcriptional regulation

DOI:  https://doi.org/10.1016/j.psj.2023.102793
Cancer Chemother Pharmacol. 2023 Jun 05.

Tumor-associated macrophages promote cisplatin resistance in ovarian cancer cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis.

Lan Hong, Xiuzhen Wang, Lang Zheng, Shengtan Wang, Genhai Zhu.

  PURPOSE: Tumor-promotive tumor-associated macrophages (TAMs) and the CXCL16/CXCR6 axis have been reported to be correlated with the limited efficacy of chemotherapy in ovarian cancer (OC). However, the role of TAM-secreted CXCL16 and the mechanism by which it affects the cisplatin (DDP) resistance of OC cells remain elusive.METHODS: We induced human THP-1 monocytes to differentiate into macrophages. Next, SKOV3 and TOV-112D cells were co-cultured with the macrophages, followed by incubation with increasing concentrations of DDP. The effects of CXCL16, CXCR6, and WTAP on the DDP resistance of OC cells were investigated using the CCK-8 assay, colony formation assay, flow cytometry, and TUNEL staining. CXCL16 concentrations were determined by ELISA. Quantitative real-time PCR and western blotting were used to examine related markers.
RESULTS: Our results showed that after being co-cultured with TAMs, the DDP resistance of OC cells was significantly enhanced and their CXCL16 levels were elevated. Acquired DDP resistance was characterized by an increased IC50 value for DDP, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of caspase-3 and Bax expression, and increased levels of Bcl-2, PARP1, BRCA1, and BRCA2 expression. Either CXCL16 knockdown in TAMs or CXCR6 knockdown in OC cells suppressed the DDP resistance of OC cells that had been co-cultured with TAMs. Knockdown of CXCL16 affected m6A RNA methylation in OC cells, as reflected by decreased YTHDF1/WTAP expression and increased ALKBH5 expression. WTAP overexpression and knockdown promoted and suppressed the DDP resistance of OC cells, respectively.
CONCLUSION: Tumor-associated macrophages promote the cisplatin resistance of OC cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis.

Keywords:  CXCL16; DDP resistance; N6-methyladenosine; Ovarian cancer; Tumor-associated macrophage; WTAP

DOI:  https://doi.org/10.1007/s00280-023-04533-8
Res Sq. 2023 May 18. pii: rs.3.rs-2745852. [Epub ahead of print]

Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease.

Lulu Jiang, Rebecca Roberts, Melissa Wong, Lushuang Zhang, Chelsea Joy Webber, Alper Kilci, Matthew Jenkins, Jingjing Sun, Guangxin Sun, Sherif Rashad, Peter C Dedon, Sarah Anne Daley, Weiming Xia, Alejandro Rondón Ortiz, Luke Dorrian, Takashi Saito, Takaomi C Saido, Benjamin Wolozin.

The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APP NL-G-F MAPT P301S mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APP NL-G-F /MAPT P301S mouse model also showed strong accumulation of N 6 -methyladenosine (m 6 A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m 6 A from mRNA, respectively. Thus, the APP NL-G-F /MAPT P301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.

DOI: https://doi.org/10.21203/rs.3.rs-2745852/v1
Hum Exp Toxicol. 2023 Jan-Dec;42:42 9603271231180856

LINC00641 impeded the malignant biological behaviors of papillary thyroid carcinoma cells via interacting with IGF2BP1 to reduce GLI1 mRNA stability.

Dongdong Meng, Shuiying Zhao, Lina Wu, Xiaojun Ma, Di Zhao, Zhifu Li.

  Dysregulation of long intergenic non-protein coding RNA 00,641 (LINC00641) is associated with the malignancy progression of multiple cancers, including thyroid carcinoma. The current study aimed to determine the role of LINC00641 in papillary thyroid carcinoma (PTC) and the underlying mechanism. We found that LINC00641 was downregulated in PTC tissues and cells(p < 0.05), and overexpression of LINC00641 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05), while silencing LINC00641 promoted the proliferation and invasion in PTC cells, and inhibited cell apoptosis(p < 0.05). Furthermore, we found that Glioma-associated oncogene homolog 1 (GLI1) expression was negatively correlated with LINC00641 expression in PTC tissues (r2 = 0.7649, p < 0.0001), and silencing GLI1 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05). Meanwhile, RNA immunoprecipitation (RIP) and RNA pull-down assays confirmed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) bound to LINC00641 as an RNA binding protein, and overexpression of LINC00641 destabilized GLI1 mRNA by competitively binding to IGF2BP1. Rescue experiments revealed that overexpression of GLI1 restored the inhibitory effect of LINC00641 overexpression on activation of the AKT pathway, as well as PTC cell proliferation and invasion, and counteracted the induction of cell apoptosis by LINC00641 overexpression. Finally, in vivo experimental results showed that overexpression of LINC00641 markedly suppressed tumor growth and reduced expression of GLI1 and p-AKT in xenograft tumor mice(p < 0.05). In summary, this study highlighted that LINC00641 plays a critical role in the malignant biological progression of PTC by regulating the LINC00641/IGF2BP1/GLI1/AKT signaling pathway, which may serve as a potential therapeutic target for PTC.

Keywords:  AKT pathway; GLI1; IGF2BP1; Linc00641; papillary thyroid carcinoma

DOI:  https://doi.org/10.1177/09603271231180856
Am J Cancer Res. 2023 ;13(5): 1640-1655

N7-methylguanosine modification: from regulatory roles to therapeutic implications in cancer.

Mengyuan Cai, Chuang Yang, Zhonglin Wang.

N7-methylguanosine (m7G) is one of the most common post-transcriptional epigenetic modifications. Different m7G methyltransferases (writers) load the m7G-cap at the 5'-terminal or inside the RNAs. For example, writers such as methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) and Williams-Beuren syndrome chromosome region 22 (WBSCR22) have been reported in mammals to promote cell proliferation, EMT, and chemoresistance in massive quantities of cancers. The underlying mechanism includes modulating the RNA secondary structure, preventing RNA degradation from exonucleases, and improving codon-dependent translation. However, some studies have shown that in colorectal and lung cancers, m7G inhibits tumor progression. m7G binding proteins (readers), such as eukaryotic translation initiation factor 4E (eIF4E), promote the efficiency of cap-dependent translation and accelerate the cell cycle to improve cancer progression. Due to the more profound understanding of m7G regulatory proteins in cancer, numerous studies aim to investigate the clinical efficiency of m7G-targeted therapy. eIF4E antisense oligonucleotide drug (4EASO) and Ribavirin are the most mature trials that competitively inhibit the binding of eIF4E to m7G-cap. These drugs have encouraging results in halting cancer progression and improving prognosis, including AML and non-small cell lung cancer, which provide a promising perspective for developing more m7G-targeted drugs. In the future, we look forward to an ongoing investigation into the role of m7G modification in tumors and drug resistance to m7G-related therapies to be solved. Therefore, the clinical application would be put into practice as soon as possible.

Keywords: N7-methylguanosine modification; RNA metabolism; cancer; cancer therapy