bims-rimeca 2023-09-24 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023–09–24
fourteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression.
m6A modification and its role in neural development and neurological diseases.
NRF1 mitigates motor dysfunction and dopamine neuron degeneration in mice with Parkinson's disease by promoting GLRX m6 A methylation through upregulation of METTL3 transcription.
NAT10 regulates the repair of UVB-induced DNA damage and tumorigenicity.
Identification of the expression patterns and potential prognostic role of m6A-RNA methylation regulators in Wilms Tumor.
FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA.
M6ATMR: identifying N6-methyladenosine sites through RNA sequence similarity matrix reconstruction guided by Transformer.
METTL3 Regulates the m6A Modification of NEK7 to Inhibit the Formation of Osteoarthritis.
YTHDF3as a prognostic predictive biomarker of thyroid cancer and its correlation with immune infiltration.
YY1 is regulated by ALKBH5-mediated m6A modification and promotes autophagy and cancer progression through targeting ATG4B.
m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance.
Targeting hnRNPC suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 in autoimmune thyroid disease.
Interaction between N6-methyladenosine modification and the tumor microenvironment in colorectal cancer.
VIRMA promotes neuron apoptosis via inducing m6A methylation of STK10 in spinal cord injury animal models.

Mol Ther. 2023 Sep 20. pii: S1525-0016(23)00501-4. [Epub ahead of print]

METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression.

Zihao Dai, Wanjie Zhu, Yingdong Hou, Xinyue Zhang, Xuxin Ren, Kai Lei, Junbin Liao, Haining Liu, Zhihang Chen, Sui Peng, Shaoqiang Li, Shuibin Lin, Ming Kuang.

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m6A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (Log rank test, p<0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m6A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m6A modification that hampers ribosome synthesis and inhibits translation of G-quadruplexes-containing mRNAs that enriched in TGF-beta pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m6A modification in ICC and unravels the mechanism of rRNA m6A modification-mediated oncogenic mRNA translation control.

DOI: https://doi.org/10.1016/j.ymthe.2023.09.014
Epigenomics. 2023 Sep 18.

m6A modification and its role in neural development and neurological diseases.

Xin Wan, Yiling Ge, Siyi Xu, Yanlu Feng, Yuxin Zhu, Lihong Yin, Yuepu Pu, Geyu Liang.

  N6-methyladenosine (m6A) methylation, the most prevalent post-transcriptional modification in eukaryotes, represents a highly dynamic and reversible process that is regulated by m6A methyltransferases, m6A demethylases and RNA-binding proteins during RNA metabolism, which affects RNA function. Notably, m6A modification is significantly enriched in the brain and exerts regulatory roles in neurogenesis and neurodevelopment through various mechanisms, further influencing the occurrence and progression of neurological disorders. This study systematically summarizes and discusses the latest findings on common m6A regulators, examining their expression, function and mechanisms in neurodevelopment and neurological diseases. Additionally, we explore the potential of m6A modification in diagnosing and treating neurological disorders, aiming to provide new insights into the molecular mechanisms and potential therapeutic strategies for neurological disorders.

Keywords:  biomarker; m6A modification; neurodevelopment; neurological disease

DOI:  https://doi.org/10.2217/epi-2023-0190
CNS Neurosci Ther. 2023 Sep 22.

NRF1 mitigates motor dysfunction and dopamine neuron degeneration in mice with Parkinson's disease by promoting GLRX m6 A methylation through upregulation of METTL3 transcription.

Xin Gong, Mengyi Huang, Lei Chen.

   OBJECTIVE: The feature of Parkinson's disease (PD) is the heavy dopaminergic neuron loss of substantia nigra pars compacta (SNpc), while glutaredoxin (GLRX) has been discovered to modulate the death of dopaminergic neurons. In this context, this study was implemented to uncover the impact of GRX1 on motor dysfunction and dopamine neuron degeneration in PD mice and its potential mechanism.
METHODS: A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. After gain- and loss-of-function assays in mice, motor coordination was assessed using rotarod, pole, and open-field tests, and neurodegeneration in mouse SNpc tissues was determined using immunohistochemistry of tyrosine hydroxylase and Nissl staining. NRF1, methyltransferase-like 3 (METTL3), and GLRX expression in SNpc tissues were evaluated using qRT-PCR, Western blot, and immunohistochemistry. The N6-methyladenosine (m6 A) levels of GLRX mRNA were examined using MeRIP. The relationship among NRF1, METTL3, and GLRX was determined by RIP, ChIP, and dual luciferase assays.
RESULTS: Low GLRX, METTL3, and NRF1 expression were observed in MPTP-induced mice, accompanied by decreased m6 A modification level of GLRX mRNA. GLRX overexpression alleviated motor dysfunction and dopamine neuron degeneration in MPTP-induced mice. METTL3 promoted m6 A modification and IGF2BP2-dependent stability of GLRX mRNA, and NRF1 increased METTL3 expression by binding to METTL3 promoter. NRF1 overexpression increased m6 A modification of GLRX mRNA and repressed motor dysfunction and dopamine neuron degeneration in MPTP-induced mice, which was counteracted by METTL3 knockdown.
CONCLUSION: Conclusively, NRF1 constrained motor dysfunction and dopamine neuron degeneration in MPTP-induced PD mice by activating the METTL3/GLRX axis.

Keywords:  IGF2BP2; Parkinson's disease; dopamine neuron degeneration; glutaredoxin; m6A methylation; methyltransferase-like 3; motor dysfunction; nuclear factor erythroid 2-like 1

DOI:  https://doi.org/10.1111/cns.14441
Toxicol Appl Pharmacol. 2023 Sep 14. pii: S0041-008X(23)00327-7. [Epub ahead of print]477 116688

NAT10 regulates the repair of UVB-induced DNA damage and tumorigenicity.

Zizhao Yang, Emma Wilkinson, Yan-Hong Cui, Haixia Li, Yu-Ying He.

  Chemical modifications in messenger RNA (mRNA) regulate gene expression and play critical roles in stress responses and diseases. Recently we have shown that N6-methyladenosine (m6A), the most abundant mRNA modification, promotes the repair of UVB-induced DNA damage by regulating global genome nucleotide excision repair (GG-NER). However, the roles of other mRNA modifications in the UVB-induced damage response remain understudied. N4-acetylcytidine (ac4C) is deposited in mRNA by the RNA-binding acetyltransferase NAT10. This NAT10-mediated ac4C in mRNA has been reported to increase both mRNA stability and translation. However, the role of ac4C and NAT10 in the UVB-induced DNA damage response remains poorly understood. Here we show that NAT10 plays a critical role in the repair of UVB-induced DNA damage lesions through regulating the expression of the key GG-NER gene DDB2. We found that knockdown of NAT10 enhanced the repair of UVB-induced DNA damage lesions by promoting the mRNA stability of DDB2. Our findings are in contrast to the previously reported role of NAT10-mediated ac4C deposition in promoting mRNA stability and may represent a novel mechanism for ac4C in the UVB damage response. Furthermore, NAT10 knockdown in skin cancer cells decreased skin cancer cell proliferation in vitro and tumorigenicity in vivo. Chronic UVB irradiation increases NAT10 protein levels in mouse skin. Taken together, our findings demonstrate a novel role for NAT10 in the repair of UVB-induced DNA damage products by decreasing the mRNA stability of DDB2 and suggest that NAT10 is a potential novel target for preventing and treating skin cancer.

Keywords:  DNA Repair; GG-NER; Global Genome Nucleotide Excision Repair; N4-Acetylcytidine mRNA Modification; NAT10; UVB-Induced DNA Damage; ac4C

DOI:  https://doi.org/10.1016/j.taap.2023.116688
BMC Med Genomics. 2023 Sep 21. 16(1): 222

Identification of the expression patterns and potential prognostic role of m6A-RNA methylation regulators in Wilms Tumor.

Changlin Jia, Hongjie Gao, Wenyue Ma, Xiaoya Liu, Mengmeng Chang, Fengyin Sun.

   BACKGROUND: To explore the potential role of m6A methylation modification in Wilms Tumor (WT) by m6A-RNA Methylation (m6A) regulators.
METHODOLOGY: The association of m6A modification patterns with immune and prognostic characteristics of tumors was systematically evaluated using 19 m6A regulators extracted from Wilms Tumor's samples in public databases. A comprehensive model of "m6Ascore" was constructed using principal component analysis, and its prognostic value was evaluated.
RESULTS: Almost all m6A regulators were differentially expressed between WT and normal tissues. Unsupervised clustering identified three distinct m6A clusters that differed in both immune cell infiltration and biological pathways. The m6Ascore was constructed to quantify m6A modifications in individual patients. Our analysis suggests that m6Ascore is an independent prognostic factor for WT and can be used as a novel predictor of WT prognosis.
CONCLUSIONS: This study comprehensively explored and systematically characterized m6A modifications in WT. m6A modification patterns play a critical role in the tumor immune microenvironment (TIME) and WT prognosis. m6Ascore provides a more comprehensive understanding of m6A modifications in WT and offers a practical tool for predicting WT prognosis. This study will help clinicians to identify valid indicators of WT to improve the poor prognosis of this disease.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://www.aliyundrive.com/drive/folder/64be739cd6956a741fb24670baeea53422be6024 .

Keywords:  Prognosis; Tumor immune microenvironment; Wilms Tumor; m6A-RNA methylation; m6Ascore

DOI:  https://doi.org/10.1186/s12920-023-01660-2
J Transl Med. 2023 Sep 22. 21(1): 652

FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA.

Yan Geng, Xinyi Long, Yuting Zhang, Yupeng Wang, Guoxing You, Wenjie Guo, Gaoming Zhuang, Yuanyuan Zhang, Xiao Cheng, Zhengqiang Yuan, Jie Zan.

   BACKGROUND: Parkinson's disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra and striatum of brain, seriously threatens human health, and is still lack of effective treatment. Dysregulation of N6-methyladenosine (m6A) modification has been implicated in PD pathogenesis. However, how m6A modification regulates dopaminergic neuronal death in PD remains elusive. Mesenchymal stem cell-derived exosomes (MSC-Exo) have been shown to be effective for treating central nervous disorders. We thus propose that the m6A demethylase FTO-targeted siRNAs (si-FTO) may be encapsulated in MSC-Exo (Exo-siFTO) as a synergistic therapy against dopaminergic neuronal death in PD.
METHODS: In this study, the effect of m6A demethylase FTO on dopaminergic neuronal death was evaluated both in vivo and in vitro using a MPTP-treated mice model and a MPP + -induced MN9D cellular model, respectively. The mechanism through which FTO influences dopaminergic neuronal death in PD was investigated with qRT-PCR, western blot, immumohistochemical staining, immunofluorescent staining and flow cytometry. The therapeutic roles of MSC-Exo containing si-FTO were examined in PD models in vivo and in vitro.
RESULTS: The total m6A level was significantly decreased and FTO expression was increased in PD models in vivo and in vitro. FTO was found to promote the expression of cellular death-related factor ataxia telangiectasia mutated (ATM) via m6A-dependent stabilization of ATM mRNA in dopaminergic neurons. Knockdown of FTO by si-FTO concomitantly suppressed upregulation of α-Synuclein (α-Syn) and downregulation of tyrosine hydroxylase (TH), and alleviated neuronal death in PD models. Moreover, MSC-Exo were utilized to successfully deliver si-FTO to the striatum of animal brain, resulting in the significant suppression of α-Syn expression and dopaminergic neuronal death, and recovery of TH expression in the brain of PD mice.
CONCLUSIONS: MSC-Exo delivery of si-FTO synergistically alleviates dopaminergic neuronal death in PD via m6A-dependent regulation of ATM mRNA.

Keywords:  Exosomes; FTO; N6-methyladenosine modification; Parkinson’s disease; siRNA

DOI:  https://doi.org/10.1186/s12967-023-04461-4
PeerJ. 2023 ;11 e15899

M6ATMR: identifying N6-methyladenosine sites through RNA sequence similarity matrix reconstruction guided by Transformer.

Shuang Xiang, Te Zhang, Minghao Wu.

  Numerous studies have focused on the classification of N6-methyladenosine (m6A) modification sites in RNA sequences, treating it as a multi-feature extraction task. In these studies, the incorporation of physicochemical properties of nucleotides has been applied to enhance recognition efficacy. However, the introduction of excessive supplementary information may introduce noise to the RNA sequence features, and the utilization of sequence similarity information remains underexplored. In this research, we present a novel method for RNA m6A modification site recognition called M6ATMR. Our approach relies solely on sequence information, leveraging Transformer to guide the reconstruction of the sequence similarity matrix, thereby enhancing feature representation. Initially, M6ATMR encodes RNA sequences using 3-mers to generate the sequence similarity matrix. Meanwhile, Transformer is applied to extract sequence structure graphs for each RNA sequence. Subsequently, to capture low-dimensional representations of similarity matrices and structure graphs, we introduce a graph self-correlation convolution block. These representations are then fused and reconstructed through the local-global fusion block. Notably, we adopt iteratively updated sequence structure graphs to continuously optimize the similarity matrix, thereby constraining the end-to-end feature extraction process. Finally, we employ the random forest (RF) algorithm for identifying m6A modification sites based on the reconstructed features. Experimental results demonstrate that M6ATMR achieves promising performance by solely utilizing RNA sequences for m6A modification site identification. Our proposed method can be considered an effective complement to existing RNA m6A modification site recognition approaches.

Keywords:  Graph; N6-methyladenosine; RNA modification; Similarity matrix; Transformer

DOI:  https://doi.org/10.7717/peerj.15899
Cartilage. 2023 Sep 19. 19476035231200336

METTL3 Regulates the m6A Modification of NEK7 to Inhibit the Formation of Osteoarthritis.

Xiaochuan Xiong, Hao Xiong, Jun Peng, Yingjie Liu, Yang Zong.

   OBJECTIVE: Osteoarthritis (OA) is a common degenerative joint disease. The occurrence of OA slowly destroys the soft tissue structure of the patient's joint. Severe cases could lead to disability. Current studies had shown that inhibition of chondrocytes pyroptosis could slow down the progression of OA. Our work aimed to explore the specific mechanisms and ways of regulating this process.
DESIGN: In this work, the level of N6-methyladenosine (m6A) in clinical tissues was detected by ribonucleic acid (RNA) m6A dot blot. qRT-PCR (quantitative real-time polymerase chain reaction) was used to detect the messenger RNA (mRNA) expression level of m6A modified enzyme in clinical tissues. MTT (3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromid) and flow cytometry were used to detect the effect of sh-METTL3 (methyltransferase like 3) and NIMA-related kinase 7 (NEK7) transfection on chondrocytes pyroptosis in OA. Western blot was used to detect the protein expression levels of pyroptosis-related proteins. ELISA (enzyme-linked immunosorbent assay) was used to measure the protein concentration of inflammatory cytokines. The SRAMP online database was used to predict the m6A site of NEK7. HE staining was used to assess the progression of OA in mice.
RESULTS: The level of m6A in clinical samples of OA patients was higher, and METTL3 was significantly higher expressed in clinical samples of OA patients. We provided evidence that low expression of METTL3 inhibited chondrocytes pyroptosis. In addition, Rescue experiments and in vivo experiments had shown that METTL3 in combination with NEK7 inhibited the progression of OA by promoting chondrocytes pyroptosis.
CONCLUSIONS: METTL3 regulates m6A modification of NEK7 and inhibits OA progression.

Keywords:  METTL3; NEK7; chondrocytes; osteoarthritis; pyroptosis

DOI:  https://doi.org/10.1177/19476035231200336
BMC Cancer. 2023 Sep 19. 23(1): 882

YTHDF3as a prognostic predictive biomarker of thyroid cancer and its correlation with immune infiltration.

Yihan Zhang, Ying Chen, Ruihua Chen, Hong Zhou, Yi Lin, Bingxin Li, Huaidong Song, Guoqiang Zhou, Mei Dong, Huanbai Xu.

   PURPOSE: Thyroid cancer (TC) is one of the most common endocrine malignancies, and its morbidity continues to rise. N6-methyladenosine (m6A) RNA methylation, an epigenetic modification, is an important regulator of gene expression in TC. Therefore, it's worth finding the characteristics and predictive value of the m6A RNA methylation regulators in thyroid cancer (TC).
METHOD: RNA-seq data of TC was downloaded from the Cancer Genome Atlas (TCGA) database to screen out the differential expressed regulators. The absolute contraction selection operator (Lasso) Cox regression was used to construct the risk model of m6A methylation regulators. The predictive value of the risk scoring model was evaluated by Kaplan Meier (K-M) analysis and receiver operating characteristic (ROC) curves. The underlying mechanism of m6A methylation regulators in TC was predicted by gene set enrichment analysis (GSEA). Further validation was performed by using immunohistochemistry (IHC) and q-PCR. The correlation between risk-related gene and immune infiltration was evaluated by Tumour Immune Estimation Resource (TIMER).
RESULTS: IGF2BP2, YTHDF1 and YTHDF3 were screened out as strong independent prognostic factors of TC. Then a risk score model was established to further screen the predictors. Finally, according to the results of overall survival (OS) and clinical characteristics of TC, YTHDF3 was screened out as a potential predictor. Meanwhile, IHC and qPCR confirmed that YTHDF3 was expressed differential in TC. The expression of YTHDF3 was positively associated with the infiltration level of CD4+ T cells and macrophages. It was strongly correlated with a variety of immune markers in TC.
CONCLUSION: We confirmed that YTHDF3 can be used as a potential prognostic biomarker of TC. It not only plays a decisive role in the initiation and development of TC, but also provides a new perspective for understanding the modification of m6A RNA in TC.

Keywords:  Biomarkers; Immune infiltration; Thyroid cancer; YTHDF3; m6A RNA methylation regulators

DOI:  https://doi.org/10.1186/s12885-023-11361-9
Aging (Albany NY). 2023 Sep 18. 15

YY1 is regulated by ALKBH5-mediated m6A modification and promotes autophagy and cancer progression through targeting ATG4B.

Shijiang Wang, Jiangbo Nie, Kaiying Xu, Yangyang Liu, Weilai Tong, Anan Li, Wei Zuo, Zhili Liu, Feng Yang.

  YY1 affects tumorigenesis and metastasis in multiple ways. However, the function of YY1 and the potential mechanisms through which it operates in gastric cancer (GC) progression by regulating autophagy remains poorly understood. This study aimed to assess the essential transcription factors (TFs) involved in autophagy regulation in GC. Western blot, RFP-GFP-LC3 double fluorescence and transmission electron microscopy (TEM) assays were used to probe autophagy activity in GC cells. Methylated RNA immunoprecipitation (MeRIP) was utilized to evaluate the ALKBH5-regulated m6A levels of YY1. Gain- and loss-of-function assays were employed in the scrutiny of the biological effects of the ALKBH5/YY1/ATG4B axis on cancer cell proliferation and invasion abilities in vitro. Per the findings, YY1 was identified as a crucial transcriptional activator of cancer autophagy-related genes and promoted the proliferation and aggressiveness of cancer cells associated with enhanced ATG4B-mediated autophagy. However, ectopic ALKBH5 expression abolished the YY1-induced effect via m6A modification. Importantly, YTHDF1 facilitated the mRNA stability of YY1 through m6A recognition. Collectively, this study found that YY1 was regulated by ALKBH5 and YTHDF1-mediated m6A modification and served as an autophagy-dependent tumor driver to accelerate cancer progression through ATG4B transactivation, providing an exploitable therapeutic target for GC.

Keywords:  ATG4B; N6-methyladenosine; YY1; autophagy; cancer

DOI:  https://doi.org/10.18632/aging.205037
Sci Total Environ. 2023 Sep 18. pii: S0048-9697(23)05829-1. [Epub ahead of print] 167202

m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance.

Jingyuan Zhang, Jinwei Song, Shuang Liu, Yuhan Zhang, Tianming Qiu, Liping Jiang, Jie Bai, Xiaofeng Yao, Ningning Wang, Guang Yang, Xiance Sun.

  Arsenic exposure has been closely linked to hepatic insulin resistance (IR) and ferroptosis with the mechanism elusive. Peroxisome proliferator γ-activated receptor coactivator 1-α (PGC-1α) is essential for glucose metabolism as well as for the production of reactive oxygen species (ROS). However, it was unclear whether there is a regulatory connection between PGC-1α and ferroptosis. Besides, the definitive mechanism of arsenic-induced hepatic IR progression remains to be determined. Here, we found that hepatic insulin sensitivity impaired by sodium arsenite (NaAsO2) could be reversed by inhibiting ferroptosis. Mechanistically, we found that PGC-1α suppression inhibited the protein expression of glutathione s-transferase kappa 1 (GSTK1) via nuclear respiratory factor 1 (NRF1), thereby increasing ROS accumulation and promoting ferroptosis. Furthermore, we showed that NaAsO2 induced hepatic IR and ferroptosis via methyltransferase-like 14 (METTL14) and YTH domain-containing family protein 2 (YTHDF2)-mediated N6-methyladenosine (m6A) of PGC-1α mRNA. In conclusion, NaAsO2-mediated PGC-1α suppression was m6A methylation-dependent and induced ferroptosis via the PGC-1α/NRF1/GSTK1 pathway in hepatic IR. The data might provide insight into potential targets for diabetes prevention and treatment.

Keywords:  Ferroptosis; Insulin resistance; N6-methyladenosine; Peroxisome proliferator γ-activated receptor coactivator 1-α; Sodium arsenite

DOI:  https://doi.org/10.1016/j.scitotenv.2023.167202
Pharmacol Res. 2023 Sep 18. pii: S1043-6618(23)00289-X. [Epub ahead of print] 106933

Targeting hnRNPC suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 in autoimmune thyroid disease.

Ke Mo, Yongli Chu, Yang Liu, Guibin Zheng, Kaiyu Song, Qiong Song, Haitao Zheng, Yuxiao Tang, Xinghan Tian, Wenjie Yao, Han Fang, Kejian Wang, Yongqiang Jiang, Dengfeng Yang, Yixuan Chen, Chengyu Huang, Ting Li, Hongmei Qu, Xicheng Song, Jin Zhou.

  Both environmental and genetic factors contribute to the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). However, the exact pathogenesis and interactions that occur between environmental factors and genes remain unclear, and therapeutic targets require further investigation due to limited therapeutic options. To solve such problems, this study utilized single-cell transcriptome, whole transcriptome, full-length transcriptome (Oxford nanopore technology), and metabolome sequencing to examine thyroid lesion tissues from 2 HT patients and 2 GD patients as well as healthy thyroid tissue from 1 control subject. HT patients had increased ATF4-positive thyroid follicular epithelial (ThyFoEp) cells, which significantly increased endoplasmic reticulum stress. The enhanced sustained stress resulted in cell death mainly including apoptosis and necroptosis. The ATF4-based global gene regulatory network and experimental validation revealed that N6-methyladenosine (m6A) reader hnRNPC promoted the transcriptional activity, synthesis, and translation of ATF4 through mediating m6A modification of ATF4. Increased ATF4 expression initiated endoplasmic reticulum stress signaling, which when sustained, caused apoptosis and necroptosis in ThyFoEp cells, and mediated HT development. Targeting hnRNPC and ATF4 notably decreased ThyFoEp cell death, thus ameliorating disease progression. Collectively, this study reveals the mechanisms by which microenvironmental cells in HT and GD patients trigger and amplify the thyroid autoimmune cascade response. Furthermore, we identify new therapeutic targets for the treatment of autoimmune thyroid disease, hoping to provide a potential way for targeted therapy.

Keywords:  ATF4; Apoptosis; Autoimmune thyroid disease; N(6)-methyladenosine; Necroptosis; hnRNPC

DOI:  https://doi.org/10.1016/j.phrs.2023.106933
Mol Med. 2023 Sep 22. 29(1): 129

Interaction between N6-methyladenosine modification and the tumor microenvironment in colorectal cancer.

Jiali Yao, Yeke Song, Xiaoping Yu, Zhijie Lin.

  The incidence and mortality of colorectal cancer (CRC) are rapidly increasing worldwide. Recently, there has been significant attention given to N6-methyladenosine (m6A), the most common mRNA modification, especially for its effects on CRC development. It is important to note that the progression of CRC would be greatly hindered without the tumor microenvironment (TME). The interaction between CRC cells and their surroundings can activate and influence complex signaling mechanisms of epigenetic changes to affect the survival of tumor cells with a malignant phenotype. Additionally, the TME is influenced by m6A regulatory factors, impacting the progression and prognosis of CRC. In this review, we describe the interactions and specific mechanisms between m6A modification and the metabolic, hypoxia, inflammatory, and immune microenvironments of CRC. Furthermore, we summarize the therapeutic role that m6A modification can play in the CRC microenvironment, and discuss the current status, limitations, and potential future directions in this field. This review aims to provide new insights into the molecular targets and theoretical foundations for the treatment of CRC.

Keywords:  Colorectal cancer; Tumor microenvironment; m6A

DOI:  https://doi.org/10.1186/s10020-023-00726-2
CNS Neurosci Ther. 2023 Sep 18.

VIRMA promotes neuron apoptosis via inducing m6A methylation of STK10 in spinal cord injury animal models.

Hongxiang Hong, Guanhua Xu, Guofeng Bao, Jinlong Zhang, Chu Chen, Jiajia Chen, Chunshuai Wu, Jiawei Jiang, Jiayi Huang, Haiming Huang, Zhiming Cui.

   BACKGROUND: Spinal cord injury (SCI) occurs as a devastating neuropathic disease. The role of serine-threonine kinase 10 (STK10) in the development of SCI remains unclear.
OBJECTIVE: This study aimed to investigate the action of m6A methylation on STK10 in the apoptosis of spinal cord neurons in the pathogenesis of SCI and the possible underlying mechanisms.
METHODS: Rat model of SCI was established and subsequently evaluated for motor function, pathological conditions, and apoptosis of spinal cord neurons. And the effects of overexpression of STK10 on neuronal cells in animal models of spinal cord injury and glyoxylate deprivation (OGD) cell models were evaluated. m6A2Target database and SRAMP database were used to predict the m6A methylation sites of STK10. The methylation kits were used to detect overall m6A methylation. Finally, the interaction between STK10 and vir like m6A methyltransferase associated (VIRMA) was explored in animal and cellular models.
RESULTS: STK10 is markedly decreased in spinal cord injury models and overexpression of STK10 inhibits neuronal apoptosis. VIRMA can induce m6A methylation of STK10. VIRMA is over-expressed in spinal cord injury models and negatively regulates the expression of STK10. m6A methylation and apoptosis of neuronal cells are reduced by the knockdown of VIRMA and STK10 shRNA have shown the opposite effects.
CONCLUSIONS: VIRMA promotes neuronal apoptosis in spinal cord injury by regulating STK10 m6A methylation.

Keywords:  STK10; VIRMA; apoptosis; m6A methylation; spinal cord injury

DOI:  https://doi.org/10.1111/cns.14453