bims-rimeca 2023-08-06 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023‒08‒06
23 papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

FTO promotes proliferation and migration of bladder cancer via enhancing stability of STAT3 mRNA in an m6A-dependent manner.
Adipose METTL14-Elicited N6 -Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing β Adrenergic Signaling and Lipolysis.
Identification of the relationship between single-cell N6-methyladenosine regulators and the infiltrating immune cells in esophageal carcinoma.
Role of METTL3 in Aerobic Glycolysis of Glioma by Regulating m6A/miR-27b-3p/PDK1.
m6A methyltransferase KIAA1429 accelerates oral squamous cell carcinoma via regulating glycolysis and ferroptosis.
Comprehensive analysis of m6A methylomes in idiopathic pulmonary arterial hypertension.
Identification of m6A-related lncRNAs-based signature for predicting the prognosis of patients with skin cutaneous melanoma.
METTL14 regulates microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke by the KAT3B-STING axis.
Prevalence and prognostic role of PD-L1 in patients with gynecological cancers: A systematic review and meta-analysis.
Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function.
Case report: A novel biallelic FTO variant causing multisystem anomalies with severe epilepsy, widening the spectrum of FTO syndrome.
Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2-dependent mechanism.
Using integrated analysis from multicentre studies to identify RNA methylation-related lncRNA risk stratification systems for glioma.
Paeoniflorin inhibits colorectal cancer cell stemness through the miR-3194-5p/catenin beta-interacting protein 1 axis.
microRNA-105-5p protects against chondrocyte injury, extracellular matrix degradation, and osteoarthritis progression by targeting SPARCL1.
LncRNA AGAP2-AS1 interacts with IGF2BP2 to promote bladder cancer progression via regulating LRG1 mRNA stability.
Melatonin supplementation promotes muscle fiber hypertrophy and regulates lipid metabolism of skeletal muscle in weaned piglets.
Demethylase FTO inhibits the development of prostate cancer by upregulating EGR2 expression in an m6A manner.
Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1.
Klf6 aggravates myocardial ischemia/reperfusion injury by activating Acsl4-mediated ferroptosis.
Circular RNA circ_0000119 promotes cervical cancer cell growth and migration via miR-433-3p/PAK2 axis.
ANGPTL2 aggravates LPS-induced septic cardiomyopathy via NLRP3-mediated inflammasome in a DUSP1-dependent pathway.
Mechanistic illustration on lipid-metabolism disorders induced by triclosan exposure from the viewpoint of m6A-RNA epigenetic modification.

Epigenetics. 2023 Dec;18(1): 2242688

FTO promotes proliferation and migration of bladder cancer via enhancing stability of STAT3 mRNA in an m6A-dependent manner.

Zhuang Sun, Xiaolu Sun, Guoliang Qin, Yi Li, Guanwen Zhou, Xianzhou Jiang.

  N6-Methyladenosine (m6A) plays a key role in the occurrence and development of various cancers. Fat mass and obesity-associated protein (FTO) was is involved in multiple cancers owing to its demethylase activity, and the molecular mechanism underlying FTO-promoted bladder cancer proliferation and migration via the regulation of RNA stability requires further investigation. In the present study, FTO was upregulated in bladder cancer and related to poor prognosis. Gain- and loss-of-function experiments showed that the upregulation of FTO promoted bladder cancer proliferation and migration. Mechanistic studies showed that FTO enhanced the stability of signal transducer and activator of transcription 3 (STAT3) mRNA in an m6A-dependent manner, thereby increasing STAT3 expression, which subsequently promoted P-STAT3 expression and activated STAT3 signalling pathway. Overall, this study revealed that the critical role of FTO in the progression of bladder cancer and could provide a novel avenue to regulate oncogene STAT3.

Keywords:  Bladder cancer; FTO; N6-methyladenosine; STAT3

DOI:  https://doi.org/10.1080/15592294.2023.2242688
Adv Sci (Weinh). 2023 Aug 01. e2301645

Adipose METTL14-Elicited N6 -Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing β Adrenergic Signaling and Lipolysis.

Qianqian Kang, Xiaorong Zhu, Decheng Ren, Alexander Ky, Ormond A MacDougald, Robert W O'Rourke, Liangyou Rui.

  White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6 -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.

Keywords:  RNA modifications; adipose tissue; diabetes; lipolysis; m6A; obesity; β-adrenergic signaling

DOI:  https://doi.org/10.1002/advs.202301645
Heliyon. 2023 Aug;9(8): e18132

Identification of the relationship between single-cell N6-methyladenosine regulators and the infiltrating immune cells in esophageal carcinoma.

Yunyi Bian, Guoshu Bi, Guangyao Shan, Jiaqi Liang, Guangyu Yao, Qihai Sui, Zhengyang Hu, Cheng Zhan, Zhencong Chen, Qun Wang.

  Background: N6-methyladenosine (m6A) RNA methylation plays a crucial role in important genomic processes in a variety of malignancies. However, the characterization of m6A with infiltrating immune cells in the tumor microenvironment (TME) in esophageal squamous carcinoma (ESCC) remains unknown.Methods: The single-cell transcriptome data from five ESCC patients in our hospital were analyzed, and TME clusters associated with prognosis and immune checkpoint genes were investigated. Cell isolation and qPCR were conducted to validate the gene characterization in different cells.
Results: According to distinct biological processes and marker genes, macrophages, T cells, and B cells clustered into three to four different subgroups. In addition, we demonstrated that m6A RNA methylation regulators were strongly related to the clinical and biological features of ESCC. Analysis of transcriptome data revealed that m6A-mediated TME cell subsets had high predictive value and showed a close relationship with immune checkpoint genes. The validation results from qPCR demonstrated the characteristics of essential genes. CellChat analysis revealed that RNA from TME cells m6A methylation-associated cell subtypes had substantial and diversified interactions with cancer cells. Further investigation revealed that MIF- (CD74+CXCR4) and MIF- (CD74+CD44) ligand-receptor pairings facilitated communication between m6A-associated subtypes of TME cells and cancer cells.
Conclusion: Overall, our study demonstrated for the first time the function of m6A methylation-mediated intercellular communication in the microenvironment of tumors in controlling tumor development and anti-tumor immune regulation in ESCC.

Keywords:  Cell communication; Esophageal squamous carcinoma; N6-methyladenosine; Single-cell; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.heliyon.2023.e18132
J Environ Pathol Toxicol Oncol. 2023 ;42(4): 31-45

Role of METTL3 in Aerobic Glycolysis of Glioma by Regulating m6A/miR-27b-3p/PDK1.

Cijie Ruan, Yuanda Zhang, Jue Zhou, Haoyuan Tan, Yinghui Bao.

Methyltransferase like 3 (METTL3) has been reported to be dysregulated in glioma. However, its role in aerobic glycolysis of glioma remains unknown. This study was conducted to explore the molecular mechanism by which METTL3 regulates aerobic glycolysis of glioma and provide novel targets for the treatment of glioma. The expression levels of METTL3, microRNA (miR)-27b-3p, and pyruvate dehydrogenase kinase 1 (PDK1) were determined in glioma cell lines and normal human astrocytes. Cell proliferation and aerobic glycolysis were evaluated by cell counting kit-8 and colony formation assays and measurements of glucose uptake, lactate production, adenosine triphosphate, Hexokinase activity, oxygen consumption rate, and extracellular acidification rate. After m6A quantification analysis, methylated RNA immunoprecipitation, and the dual-luciferase assay, the rescue experiments were performed using miR-27b-3p inhibitor or pcDNA3.1-PDK1 with pcDNA3.1-METTL3. METTL3 was lower in glioma cells and METTL3 overexpression reduced aerobic glycolysis. METTL3 increased m6A modification to promote the processing of pri-miR-27b by DGCR8 and the expression of mature miR-27b-3p, and miR-27b-3p targeted and inhibited PDK1 expression. miR-27b-3p inhibition or PDK1 overexpression both neutralized the inhibitory role of METTL3 overexpression in aerobic glycolysis. Overall, METTL3 overexpression increased the expression of mature miR-27b-3p via m6A modification and inhibited PDK1 expression, thus suppressing aerobic glycolysis of glioma.

DOI: https://doi.org/10.1615/JEnvironPatholToxicolOncol.2023046521
Transl Oncol. 2023 Jul 28. pii: S1936-5233(23)00131-6. [Epub ahead of print]36 101745

m6A methyltransferase KIAA1429 accelerates oral squamous cell carcinoma via regulating glycolysis and ferroptosis.

Ke Xu, Xiaojuan Dai, Jincheng Yue.

  N6-methyladenosine (m6A) modification acts as the most prevalent modification on eukaryotic RNA, and its function on oral squamous cell carcinoma (OSCC) is still unclear. Here, the present research aimed to explore the novel function of m6A methyltransferase KIAA1429 in OSCC. Results illustrated that KIAA1429 up-regulated in the OSCC samples and cells. Gain/loss functional assays demonstrated that KIAA1429 repressed the ferroptosis of OSCC. Moreover, KIAA1429 positively accelerated the aerobic glycolysis of OSCC, including glucose uptake, lactate production, ATP level and ECAR. Mechanistically, KIAA1429 could install the m6A modification on the PGK1 mRNA, thereby up-regulating the methylated m6A level. Moreover, m6A reader YTHDF1 recognized the m6A modification site of PGK1 mRNA and enhanced its mRNA stability. Thus, KIAA1429 promoted the OSCC aerobic glycolysis and inhibited the ferroptosis of OSCC through YTHDF1-mediated PGK1 mRNA stability. Taken together, these findings reveal a novel insight for KIAA1429 on OSCC via m6A-dependent manner.

Keywords:  Aerobic glycolysis; Ferroptosis; KIAA1429; N(6)-methyladenosine; Oral squamous cell carcinoma

DOI:  https://doi.org/10.1016/j.tranon.2023.101745
Epigenetics. 2023 Dec;18(1): 2242225

Comprehensive analysis of m6A methylomes in idiopathic pulmonary arterial hypertension.

Ting Huang, Yunhong Zeng, Yao Yang, Haoqin Fan, Youcai Deng, Wenjuan Chen, Jinqiao Liu, Fan Yang, Wenfeng Li, Yunbin Xiao.

  Idiopathic pulmonary arterial hypertension (IPAH) is a serious and fatal disease. Recently, m6A has been reported to play an important role in the lungs of IPAH patients and experimental pulmonary hypertension models. However, the meaning of m6A mRNAs in the peripheral blood of IPAH patients remains largely unexplored. We aimed to construct a transcriptome-wide map of m6A mRNAs in the peripheral blood of IPAH patients. M6A RNA Methylation Quantification Kit was utilized to measure the total m6A levels in the peripheral blood of IPAH patients. A combination of MeRIP-seq, RNA-seq and bioinformatics analysis was utilized to select m6A-modified hub genes of IPAH. MeRIP-qPCR and RT-qPCR were used to measure the m6A levels and mRNA levels of TP53, RPS27A, SMAD3 and FoxO3 in IPAH patients. Western blot was performed to assess the protein levels of m6A related regulators and m6A related genes in experimental PH animal models, hypoxia-treated and PDGF-BB induced PASMCs. We found that the total m6A levels were increased in peripheral blood of IPAH patients and verified that m6A levels of RPS27A and SMAD3 were significantly elevated and m6A levels of TP53 and FoxO3 were significantly reduced. The mRNA or protein levels of RPS27A, SMAD3, TP53 and FoxO3 were changed in human blood samples, experimental PH animal models and PDGF-BB induced PASMCs. Moreover, METTL3 and YTHDF1 were increased in the hypoxia induced pulmonary hypertension rat model, hypoxia-treated and PDGF-BB induced PASMCs. These finding suggested that m6A may play an important role in IPAH.

Keywords:  FoxO3; METTL3; N6-methyladenosine; RPS27A; SMAD3; TP53; YTHDF1; idiopathic pulmonary arterial hypertension

DOI:  https://doi.org/10.1080/15592294.2023.2242225
SLAS Technol. 2023 Aug 02. pii: S2472-6303(23)00051-1. [Epub ahead of print]

Identification of m6A-related lncRNAs-based signature for predicting the prognosis of patients with skin cutaneous melanoma.

Wentao Lin, Zhou-Yong Tan, Xi-Chi Fang.

  BACKGROUND: Skin cutaneous melanoma (SKCM) is one of the fastest developing malignancies with strong aggressive ability and no proper curative treatments. Numerous studies illustrated the importance of N6-methyladenosine (m6A) RNA modification to tumorigenesis. The aim of this study was to identify novel prognostic signature by using m6A-related lncRNAs, thus to improve the survival for SKCM patients and guide SKCM therapy.METHODS: We downloaded the Presentational Matrix data from The Cancer Genome Atlas (TCGA) and analyzed all the expressed lncRNAs among 468 SKCM samples. Pearson correlation analysis was performed to assess the correlations between lncRNAs and 29 m6A-related genes. Least absolute shrinkage and selection operator (LASSO), univariate and multivariate Cox regression analysis were performed to construct m6A-related lncRNAs prognostic signature (m6A-LPS). The accuracy and prognostic value of this signature were validated by using receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) survival analysis, univariate COX or multivariate COX analyses. After calculating risk scores, patients were divided into low- and high-risk subgroups by the median value of risk scores.
RESULTS: A total of 2973 lncRNAs were found expressed among SKCM tissues. Prognostic analysis showed that 98 lncRNAs had a significant effect on the survival of SKCM patients. The m6A-LPS was validated using K-M and ROC analysis and the predictive accuracy of the risk score was also high according to the AUC of the ROC curve in training and testing sets. A nomogram based on tumor stage, gender and risk score that had a strong ability to forecast the 1-, 2-, 3-, 5-year OS of SKCM patients confirmed by calibrations. Enrichment analysis indicated that malignancy-associated biological processes and pathways were more common in the high-risk subgroup.
CONCLUSION: Collectively, m6A-related lncRNAs exert as potential biomarkers for prognostic stratification of SKCM patients and may assist clinicians achieving individualized treatment for SKCM.

Keywords:  N6-methyladenosine (m6a); Skin cutaneous melanoma; lncRNAs; prognostic signature

DOI:  https://doi.org/10.1016/j.slast.2023.08.001
Neurobiol Dis. 2023 Aug 02. pii: S0969-9961(23)00268-1. [Epub ahead of print] 106253

METTL14 regulates microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke by the KAT3B-STING axis.

Yamei Li, Jiacen Li, Qian Yu, Ling Ji, Bo Peng.

  N6-methyladenosine (m6A) plays a crucial role in ischemic stroke, whereas the role of methyltransferase-like 14 (METTL14) in ischemic stroke remains unknown. A model of middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation/reperfusion (OGD/R) model in HAPI cells were used to simulate ischemic stroke in vivo and in vitro. We found that METTL14 level was upregulated in microglia/macrophage after MCAO and OGD/R. METTL14 enhanced the expression of KAT3B by promoting the m6A modification of KAT3B mRNA. STING has been identified as a target for KAT3B and KAT3B increased STING expression by enhancing H3K27ac in the STING promoter. METTL14 promoted M1 polarization and NLRP3 inflammasome/pyroptosis axis by the KAT3B-STING signaling after OGD/R. METTL14 depletion relieved brain injury by inhibiting M1-like microglia/macrophage polarization and NLRP3 inflammasome/pyroptosis axis in MCAO rats. These findings indicate that METTL14 depletion relieves MCAO-induced brain injury, probably via switching microglia/macrophage from M1 towards M2 and restraining NLRP3 inflammasome/pyroptosis axis in microglia/macrophage.

Keywords:  Ischemic stroke; METTL14; Microglial polarization; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.nbd.2023.106253
Crit Rev Oncol Hematol. 2023 Aug 01. pii: S1040-8428(23)00172-5. [Epub ahead of print]189 104084

Prevalence and prognostic role of PD-L1 in patients with gynecological cancers: A systematic review and meta-analysis.

Hanlin Fu, Zhihui Fu, Meng Mao, Lulu Si, Jing Bai, Qian Wang, Ruixia Guo.

  OBJECTIVE: Our study aims to evaluate programmed cell death ligand-1 (PD-L1) expression and its prognostic significance in cervical cancer (CC), endometrial cancer (EC) and ovarian cancer (OC).METHODS: Several electronic databases were searched. Fixed effects models or random effects models were employed to calculate the pooled prevalence of PD-L1 positivity and pooled hazard ratios (HRs) as appropriate. Heterogeneity and publication bias were also assessed.
RESULTS: The pooled prevalence of PD-L1 positivity was 58.1%, 33.8% and 37.5% for CC, EC and OC patients, respectively. There were significant differences in the pooled estimates after stratification by PD-L1-positive assessment criteria and antibody clones. PD-L1 positivity was associated with worse OS in CC and EC patients and poorer progression-free survival (PFS) in CC patients.
CONCLUSIONS: The prevalence of PD-L1-positive expression was considerably high in CC and modestly high in EC and OC patients. PD-L1 expression has the potential to be a prognostic biomarker for predicting the clinical outcomes of patients with CC and EC but not OC.

Keywords:  Gynecological cancers; Prevalence; Prognosis; Programmed cell death ligand-1; Systematic review

DOI:  https://doi.org/10.1016/j.critrevonc.2023.104084
Redox Biol. 2023 Jul 24. pii: S2213-2317(23)00225-2. [Epub ahead of print]65 102824

Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function.

Fanglin Niu, Zhuozhuo Li, Yuanyuan Ren, Zi Li, Hua Guan, Yang Li, Yan Zhang, Yirong Li, Junle Yang, Lu Qian, Wenzhen Shi, Xiaobin Fan, Jinli Li, Lele Shi, Yi Yu, Yuyan Xiong.

  Vascular endothelial cells (ECs) senescence plays a crucial role in vascular aging that promotes the initiation and progression of cardiovascular disease. The mutation of Grb10-interacting GYF protein 2 (GIGYF2) is strongly associated with the pathogenesis of aging-related diseases, whereas its role in regulating ECs senescence and dysfunction still remains elusive. In this study, we found aberrant hyperexpression of GIGYF2 in senescent human ECs and aortas of old mice. Silencing GIGYF2 in senescent ECs suppressed eNOS-uncoupling, senescence, and endothelial dysfunction. Conversely, in nonsenescent cells, overexpressing GIGYF2 promoted eNOS-uncoupling, cellular senescence, endothelial dysfunction, and activation of the mTORC1-SK61 pathway, which were ablated by rapamycin or antioxidant N-Acetyl-l-cysteine (NAC). Transcriptome analysis revealed that staufen double-stranded RNA binding protein 1 (STAU1) is remarkably downregulated in the GIGYF2-depleted ECs. STAU1 depletion significantly attenuated GIGYF2-induced cellular senescence, dysfunction, and inflammation in young ECs. Furthermore, we disclosed that GIGYF2 acting as an RNA binding protein (RBP) enhances STAU1 mRNA stability, and that the intron region of the late endosomal/lysosomal adaptor MAPK and mTOR activator 4 (LAMTOR4) could bind to STAU1 protein to upregulate LAMTOR4 expression. Immunofluorescence staining showed that GIGYF2 overexpression promoted the translocation of mTORC1 to lysosome. In the mice model, GIGYF2flox/flox Cdh-Cre+ mice protected aged mice from aging-associated vascular endothelium-dependent relaxation and arterial stiffness. Our work discloses that GIGYF2 serving as an RBP enhances the mRNA stability of STAU1 that upregulates LAMTOR4 expression through binding with its intron region, which activates the mTORC1-S6K1 signaling via recruitment of mTORC1 to the lysosomal membrane, ultimately leading to ECs senescence, dysfunction, and vascular aging. Disrupting the GIGYF2-STAU1-mTORC1 signaling cascade may represent a promising therapeutic approach against vascular aging and aging-related cardiovascular diseases.

Keywords:  Endothelial cell senescence; Endothelial dysfunction; Signaling; Vascular aging; eNOS uncoupling

DOI:  https://doi.org/10.1016/j.redox.2023.102824
SAGE Open Med Case Rep. 2023 ;11 2050313X231188883

Case report: A novel biallelic FTO variant causing multisystem anomalies with severe epilepsy, widening the spectrum of FTO syndrome.

Naomi Mayman, Jiangbo Wei, Shangjun Cai, Rohan Soman, Hillary Raynes, Maite La Vega-Talbott, Chuan He, Thomas Naidich, G Praveen Raju, Sathiji Kathiresu Nageshwaran.

  The fat mass and obesity-associated gene (FTO) codes for a DNA/RNA demethylase. Pathological variants in this gene are rare, with only three reports in the literature, all with mutations in the catalytic domain. We report the first biallelic human variant in fat mass and obesity-associated gene (c.287G>C, p.Arg96Pro/R96P) outside the catalytic site, causing numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function. Biochemical assays of cells with the patient's variant were performed to further quantify the effect of the variant on function. Loss-of-function resulting from the patient's R96P missense variant was demonstrated with in vitro biochemical characterization of demethylase activity, resulting in a 90% reduction in function of the fat mass and obesity-associated protein compared to wild-type. Our findings demonstrate a novel fat mass and obesity-associated gene non-catalytic site variant with a unique patient phenotype of bilateral multifocal epilepsy and multisystem congenital anomalies.

Keywords:  DNA/RNA demethylase; FTO; FTO congenital malformation syndrome; brain malformation; fat mass and obesity-associated gene; intractable epilepsy

DOI:  https://doi.org/10.1177/2050313X231188883
Clin Transl Med. 2023 Aug;13(8): e1359

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2-dependent mechanism.

Wei-Jian Ni, Hong Zhou, Hao Lu, Nan-Nan Ma, Bing-Bing Hou, Wei Li, Fan-Xu Kong, Ju-Tao Yu, Rui Hou, Juan Jin, Jia-Gen Wen, Tao Zhang, Xiao-Ming Meng.

  BACKGROUND: N6 -methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator-mediated m6A modification during renal fibrosis and thereby explore promising anti-renal fibrosis agents.METHODS: Renal tissues from humans and mice as well as HK-2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real-time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase-like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP-like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti-renal fibrosis.
RESULTS: METTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK-2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7-induced suppression of transforming growth factor-β (TGF-β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti-renal fibrosis effects.
CONCLUSIONS: Collectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti-renal fibrosis agent.

Keywords:  N6-methyladenosine (m6A); chronic kidney disease; insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2); methyltransferase-like 3 (METTL3); renal fibrosis; traditional Chinese medicine

DOI:  https://doi.org/10.1002/ctm2.1359
Cancer Cell Int. 2023 Aug 05. 23(1): 156

Using integrated analysis from multicentre studies to identify RNA methylation-related lncRNA risk stratification systems for glioma.

Fanxuan Huang, Xinyu Wang, Junzhe Zhong, Hao Chen, Dan Song, Tianye Xu, Kaifu Tian, Penggang Sun, Nan Sun, Jie Qin, Yu Song, Wenbin Ma, Yuxiang Liu, Daohan Yu, Xiangqi Meng, Chuanlu Jiang, Hanwen Xuan, Da Qian, Jinquan Cai.

  BACKGROUND: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether RNA methylation-related long noncoding RNAs (lncRNAs) affect the prognosis of glioma.METHODS: We summarized 32 m6A/m5C/m1A-related genes and downloaded RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed (DE-) RNA methylation-related lncRNAs in order to construct a prognostic signature of glioma and in order to determine their correlation with immune function, immune therapy and drug sensitivity. In vitro and in vivo assays were performed to elucidate the effects of RNA methylation-related lncRNAs on glioma.
RESULTS: A total of ten RNA methylation-related lncRNAs were used to construct a survival and prognosis signature, which had good independent prediction ability for patients. It was found that the high-risk group had worse overall survival (OS) than the low-risk group in all cohorts. In addition, the risk group informed the immune function, immunotherapy response and drug sensitivity of patients with glioma in different subgroups. Knockdown of RP11-98I9.4 and RP11-752G15.8 induced a more invasive phenotype, accelerated cell growth and apparent resistance to temozolomide (TMZ) both in vitro and in vivo. We observed significantly elevated global RNA m5C and m6A levels in glioma cells.
CONCLUSION: Our study determined the prognostic implication of RNA methylation-related lncRNAs in gliomas, established an RNA methylation-related lncRNA prognostic model, and elucidated that RP11-98I9.4 and RP11-752G15.8 could suppress glioma proliferation, migration and TMZ resistance. In the future, these RNA methylation-related lncRNAs may become a new choice for immunotherapy of glioma.

Keywords:  Chemotherapy; Glioma; Immunotherapy; LncRNAs; Prognosis; RNA methylation

DOI:  https://doi.org/10.1186/s12935-023-03001-w
Kaohsiung J Med Sci. 2023 Aug 02.

Paeoniflorin inhibits colorectal cancer cell stemness through the miR-3194-5p/catenin beta-interacting protein 1 axis.

Zhao Su, Beier Hu, Jing Li, Zhichun Zeng, Hu Chen, Yuhang Guo, Yun Mao, Wen Cao.

  Paeoniflorin (PF) is a natural plant ingredient with remarkable antitumor effects. Herein, we investigated the biological effects and mechanism of PF in colorectal cancer (CRC) cell stemness. The messenger RNA (mRNA) and protein expressions were assessed using quantitative real-time polymerase chain reaction and western blot. The viability, proliferation, and migration and invasion of CRC cells were evaluated using cell counting kit-8, clone-formation, and transwell migration and invasion assays, respectively. The sphere-formation capacity was determined using the sphere-formation assay. A dual-luciferase reporter gene assay was employed to analyze the interaction between miR-3194-5p and catenin beta-interacting protein 1 (CTNNBIP1). The viability, migration, invasion, epithelial-mesenchymal transition, and stemness of CRC cells were repressed by PF. MiR-3194-5p was upregulated in CRC tissues and cells. MiR-3194-5p knockdown suppressed CRC cell stemness, while miR-3194-5p overexpression had the opposite effect. In addition, the inhibition of CRC cell stemness caused by PF was eliminated by miR-3194-5p overexpression. CTNNBIP1 functioned as the target of miR-3194-5p, whose knockdown abrogated the repression of CRC cell stemness and Wnt/β-catenin signaling activation by PF.PF regulated the miR-3194-5p/CTNNBIP1/Wnt/β-catenin axis to repress CRC cell stemness.

Keywords:  CTNNBIP1; colorectal cancer; miR-3194-5p; paeoniflorin; stemness

DOI:  https://doi.org/10.1002/kjm2.12736
Histol Histopathol. 2023 Jul 26. 18654

microRNA-105-5p protects against chondrocyte injury, extracellular matrix degradation, and osteoarthritis progression by targeting SPARCL1.

Dong Jiang, Shigao Cheng, Pengcheng Kang, Tengfei Li, Xun Li, Jiongzhe Xiao, Lian Ren.

OBJECTIVE: Both microRNA (miR)-105-5p and SPARCL1 were discovered to be differentially expressed in osteoarthritis (OA), but their roles and exact mechanisms have not been entirely elaborated. This paper sets out to probe the impact of miR-105-5p/SPARCL1 on chondrocyte injury, extracellular matrix degradation, and osteoarthritis progression.METHODS: C28/I2 cells were stimulated with IL-1β to construct an in vitro OA model. C28/I2 cells were transfected with sh-SPARCL1, oe-SPARCL1, or miR-105-5p mimic before IL-1β induction. CCK-8 assay, flow cytometry, and ELISA were adopted to assess cell viability, apoptosis, and inflammatory factor expression, respectively. The binding relationship of miR-105-5p to SPARCL1 was assessed using dual-luciferase reporter assay. After an OA rat model was established, rats underwent intra-articular injection with ago-miR-105-5p. TUNEL was applied to determine cell apoptosis in vivo. mRNA and protein levels were measured by qRT-PCR and western blot, respectively, in vitro and in vivo.
RESULTS: IL-1β treatment diminished miR-105-5p expression and augmented SPARCL1 expression in C28/I2 cells. miR-105-5p decreased SPARCL1 expression by targeting SPARCL1. miR-105-5p overexpression or SPARCL1 silencing prominently reversed the decrease in viability and the promotion of inflammatory factor production, cartilage matrix degradation, and apoptosis in IL-1β-stimulated C28/I2 cells. Furthermore, upregulation of SPARCL1 nullified the influence of miR-105-5p overexpression on viability, apoptosis, inflammation, and cartilage matrix degradation in IL-1β-stimulated C28/I2 cells. miR-105-5p overexpression ameliorated knee cartilage tissue injury in OA rats.
CONCLUSION: Conclusively, miR-105-5p exerted suppressive effects on chondrocyte injury, extracellular matrix degradation, and OA progression by targeting SPARCL1.

DOI: https://doi.org/10.14670/HH-18-654
Cell Signal. 2023 Aug 02. pii: S0898-6568(23)00253-X. [Epub ahead of print] 110839

LncRNA AGAP2-AS1 interacts with IGF2BP2 to promote bladder cancer progression via regulating LRG1 mRNA stability.

Xu Zhao, Jinbo Chen, Chunyu Zhang, Guoou Xie, Belaydi Othmane, Xiaogen Kuang, Bolong Liu.

  BACKGROUND: The long non-coding RNA (lncRNA) AGAP2-AS1 was implicated in tumorigenesis, yet with unclear mechanism in the development of Bladder Cancer (BCa).METHODS: We collected the clinicopathological features and tissue samples of 45 patients with BCa in Xiangya Hospital. Expressions of AGAP2-AS1 and LRG1 were detected by RT-qPCR in BCa tissues and normal tissues as well as in BCa cells. The roles of AGAP2-AS1 and LRG1 were investigated by CCK-8, colony formation assay, transwell assays and tube formation assay. The subcellular localization of AGAP2-AS1 was detected by Fluorescence in situ hybridization. Bioinformatics method, RNA immunoprecipitation, RNA pull-down assay and Actinomycin D test were used to predict and identify the relationships between AGAP2-AS1, LRG1 and IGF2BP2. Xenografted tumors were produced to explore the function of AGAP2-AS1 in BCa in vivo.
RESULTS: AGAP2-AS1 and LRG1 were highly upregulated in BCa. AGAP2-AS1 positively correlated with T stage, grade and vascular invasion, but negatively correlated with the survival of patients. Overexpressions of AGAP2-AS1 promoted proliferation, migration, invasion, tumor angiogenesis in vitro and tumor growth, metastasis in vivo, knockdown of AGAP2-AS1 exhibited the opposite effects. AGAP2-AS1 localized mainly in the cytoplasm. AGAP2-AS1 directly bound to IGF2BP2 protein to enhance LRG1 mRNA stability. Inhibition of BCa progression by AGAP2-AS1 knockdown may be reversed by LRG1 overexpression.
CONCLUSION: AGAP2-AS1 can promote BCa progression and metastasis by recruiting IGF2BP2 to stabilize LRG1.

Keywords:  AGAP2-AS1; Bladder cancer; IGF2BP2; LRG1; Long non-coding RNA

DOI:  https://doi.org/10.1016/j.cellsig.2023.110839
J Anim Sci. 2023 Aug 02. pii: skad256. [Epub ahead of print]

Melatonin supplementation promotes muscle fiber hypertrophy and regulates lipid metabolism of skeletal muscle in weaned piglets.

Wentao Chen, Yuang Tu, Peiran Cai, Liyi Wang, Yanbing Zhou, Shiqi Liu, Yuqin Huang, Shu Zhang, Xin Gu, Wuzhou Yi, Tizhong Shan.

  Melatonin has been reported to play crucial roles in regulating meat quality, improving reproductive properties and maintaining intestinal health in animal production, but whether it regulates skeletal muscle development in weaned piglet is rarely studied. This study was conducted to investigate the effects of melatonin on growth performance, skeletal muscle development and lipid metabolism in animals by intragastric administration of melatonin solution. Twelve 28-day-old DLY (Duroc × Landrace × Yorkshire) weaned piglets with similar body weight were randomly divided into two groups: control group and melatonin group. The results showed that melatonin supplementation for 23 days had no effect on growth performance, but significantly reduced serum glucose content (P<0.05). Remarkably, melatonin increased longissimus dorsi muscle (LDM) weight, eye muscle area and decreased the liver weight in weaned piglets (P<0.05). In addition, the cross-sectional area of muscle fibers was increased (P<0.05), while triglyceride (TG) levels were decreased in LDM and psoas major muscle (PMM) by melatonin treatment (P<0.05). Transcriptome sequencing showed melatonin induced the expression of genes related to skeletal muscle hypertrophy and fatty acid oxidation. Enrichment analysis indicated that melatonin regulated cholesterol metabolism, protein digestion and absorption and mitophagy signaling pathways in muscle. Gene set enrichment analysis (GSEA) also confirmed the effects of melatonin on skeletal muscle development and mitochondrial structure and function. Moreover, quantitative real-time polymerase chain reaction (qPCR) analysis revealed that melatonin supplementation elevated the gene expression of cell differentiation and muscle fiber development, including paired box 7 (PAX7), myogenin (MYOG), myosin heavy chain (MYHC) ⅡA and MYHC ⅡB (P<0.05), which was accompanied by increased insulin like growth factor 1 (IGF1) and insulin like growth factor binding protein 5 (IGFBP5) expression in LDM (P<0.05). Additionally, melatonin regulated lipid metabolism and activated mitochondrial function in muscle by increasing the mRNA abundance of cytochrome c oxidase subunit 6A (COX6A), COX5B and carnitine palmitoyltransferase 2 (CPT2) and decreasing the mRNA expression of peroxisome proliferator activated receptor gamma (PPARG), Acetyl-CoA carboxylase (ACC) and fatty acid binding protein 4 (FABP4) (P<0.05). Together, our results suggest that melatonin could promote skeletal muscle growth and muscle fiber hypertrophy, improve mitochondrial function and decrease fat deposition in muscle.

Keywords:  Growth performance; Lipid metabolism; Melatonin; Muscle development; Muscle fiber hypertrophy; Weaned piglet

DOI:  https://doi.org/10.1093/jas/skad256
Turk J Biol. 2022 ;46(6): 426-438

Demethylase FTO inhibits the development of prostate cancer by upregulating EGR2 expression in an m6A manner.

Zhenyu Wang, Huamin Sun, Hua Zhu, Donghua Gu, Xinfeng Chen, Yongsheng Pan, Bing Zheng, Dongrong Yang.

  Fat mass and obesity-associated protein (FTO) is a demethylase and plays a vital role in various cancers. However, the regulation mechanism of FTO in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanism of FTO in PCa. The function and mechanism of FTO-mediated in PCa were determined by gain-of-function assays and RNA-seq. We found that FTO expression in PCa tissues and two PCa cell lines were significantly lower than that in adjacent tissues and normal cell line. PCa cells after overexpression of FTO showed a significant lower in proliferation, migration, and invasion capabilities. RNA-seq displayed that FTO overexpression altered transcriptome landscape in Du145 and PC-3 cells, particularly upregulating EGR2 expression. FTO overexpression induced differential expression genes, including MYLK2, DNA2, CDK, and CDC (6, 7, 20, 25, and 45), which were mainly enriched in adjustment of cell cycle and growth pathways. Furthermore, FTO overexpression significantly reduced the EGR2 methylation level. Arresting the proliferation, migration, and invasion of Du145 cells induced by FTO overexpression was significantly rescued by EGR2 knockdown. FTO overexpression also significantly inhibited tumor growth and promoted EGR2 protein expression. Taken together, FTO suppresses PCa progression by regulating EGR2 methylation. We uncovered a novel regulatory mechanism of FTO in PCa and provide a new potential therapeutic target for PCa.

Keywords:  EGR2; FTO; Prostate cancer; demethylase

DOI:  https://doi.org/10.55730/1300-0152.2629
iScience. 2023 Aug 18. 26(8): 107315

Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1.

Xiangyu Tan, Xueqian Wang, Xueyao Liao, Xin Wang, Zhichao Jiang, Wenjia Liang, Chen Cao, Danni Gong, Zheng Hu, Xun Tian.

  Cisplatin resistance remains a major obstacle limiting the effectiveness of chemotherapy in cervical cancer. However, the underlying mechanism of cisplatin resistance is still unclear. In this study, we demonstrate that vacuolar protein sorting 13 homolog C (VPS13C) deficiency promotes cisplatin resistance in cervical cancer. Moreover, through an RNA sequencing screen, VPS13C deficiency was identified as negatively correlated with the high expression of glutathione S-transferase pi gene (GSTP1). Mechanistically, loss of VPS13C contributes to cisplatin resistance by influencing the expression of GSTP1 and inhibiting the downstream c-Jun N-terminal kinase (JNK) pathway. In addition, targeting GSTP1 with the inhibitor NBDHEX effectively rescued the cisplatin resistance induced by VPS13C deficiency. Overall, our findings provide insights into the underlying mechanisms of VPS13C in cisplatin resistance and identify VPS13C as a promising candidate for the treatment of chemoresistance in cervical cancer.

Keywords:  Cancer; Molecular biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107315
Kaohsiung J Med Sci. 2023 Aug 02.

Klf6 aggravates myocardial ischemia/reperfusion injury by activating Acsl4-mediated ferroptosis.

Ma-Li Qiu, Wei Yan, Mo-Mu Liu.

  Ferroptosis is closely related to myocardial ischemia/reperfusion (I/R) damage. Kruppel-like factor 6 (Klf6) can aggravate renal I/R injury. We aimed to elucidate the role of Klf6 in myocardial I/R damage as well as its potential mechanism. Myocardial I/R mice model and hypoxia/reoxygenation (H/R)-treated HL-1 cells were established. The levels of Fe2+ , MDA, lipid ROS, and ferroptosis-related proteins were measured for assessing ferroptosis. Infarct area, H&E staining, cardiac function, and cell viability were detected for evaluating myocardial injury. Immunohistochemistry, immunofluorescence, western blot, and RT-qPCR were applied for detecting the levels of related genes. The m6A modification of Klf6, as well as the relationships between Klf6 and Mettl3, Igf2bp2, or Acsl4 promoter, was evaluated using MeRIP, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assay accordingly.Klf6 protein and mRNA levels, as well as Klf6 m6A modification, were elevated in HL-1 cells subjected to H/R and in the heart tissues from I/R mice. In H/R-challenged HL-1 cells, the binding relationships between Klf6 mRNA and Igf2bp2 or Mettl3 were confirmed; moreover, Igf2bp2 or Mettl3 knockdown decreased the Klf6 level and inhibited Klf6 mRNA stability. Klf6 knockdown restrained H/R-triggered cell viability loss, improved I/R-induced myocardial injury, and inhibited ferroptosis in myocardial I/R damage models. Klf6 directly bound to the Acsl4 promoter and positively regulated its expression. Acsl4 overexpression compromised the Klf6 knockdown-generated protective effect in HL-1 cells.m6A modification-regulated Klf6 aggravated myocardial I/R damage through activating Acsl4-mediated ferroptosis, thereby providing one potential target for the treatment of myocardial I/R.

Keywords:  Acsl4; Klf6; ferroptosis; m6A modification; myocardial ischemia/reperfusion

DOI:  https://doi.org/10.1002/kjm2.12733
J Appl Genet. 2023 Aug 04.

Circular RNA circ_0000119 promotes cervical cancer cell growth and migration via miR-433-3p/PAK2 axis.

Junxiao Zhang, Guanghua Chu, Lihua Zheng, Juandi Liu, Juxian He.

  The purpose of this study was to investigate the role of circ_0000119 on CC progression and its molecular mechanism. The expression levels of circ_0000119, miR-433-3p, and p21-activated kinase 2 (PAK2) in CC tissues and cell lines were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was assessed using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay and colony formation assay. Cell cycle and apoptosis were assessed by flow cytometry. Cell migration and invasive ability were examined by Transwell assays. Downstream binding targets of circ_0000119 were predicted by online bioinformatics tools and confirmed by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay. The role of circ_0000119/miR-433-3p/PAK2 axis in regulating the CC process was explored by rescue experiments. A xenograft model was constructed to further determine the effect of circ_0000119 on CC tumor growth in vivo. Immunohistochemistry (IHC) assay was conducted for Ki67 expression. Circ_0000119 was aberrantly upregulated in CC tissues and cell lines. Knockdown of circ_0000119 inhibited CC cell proliferation, cell cycle progress, migration, invasion, and promoted apoptosis of CC cells. MiR-433-3p was a binding target of circ_0000119, and PAK2 was a downstream gene of miR-433-3p. MiR-433-3p inhibition reversed the inhibitory effect of silencing circ_0000119 on CC progression. In addition, PAK2 overexpression reversed the effect of miR-433-3p on CC progression. PAK2 expression was regulated by circ_0000119 and miR-433-3p. Moreover, circ_0000119 knockdown reduced tumor growth of CC in vivo. Circ_0000119 was upregulated in CC, and circ_0000119 knockdown suppressed CC malignant development through the miR-433-3p/PAK2 axis.

Keywords:  CC; PAK2; circ_0000119; miR-433-3p

DOI:  https://doi.org/10.1007/s13353-023-00772-w
Int Immunopharmacol. 2023 Jul 31. pii: S1567-5769(23)01026-3. [Epub ahead of print]123 110701

ANGPTL2 aggravates LPS-induced septic cardiomyopathy via NLRP3-mediated inflammasome in a DUSP1-dependent pathway.

Jun Li, Ting Wan, Cheng Liu, Huadong Liu, Dong Ke, Luocheng Li.

  Angiopoietin-like protein 2 (ANGPTL2) was implicated in various cardiovascular diseases; however, its role in lipopolysaccharide (LPS)-related septic cardiomyopathy remains unclear. Herein, mice were exposed to LPS to generate septic cardiomyopathy, and adeno-associated viral vector was employed to overexpress ANGPTL2 in the myocardium. Besides, mice were treated with adenoviral vector to knock down ANGPTL2 in hearts. ANGPTL2 expressions in hearts and cardiomyocytes were upregulated by LPS challenge. ANGPTL2 overexpression aggravated, while ANGPTL2 silence ameliorated LPS-associated cardiac impairment and inflammation. Mechanically, we found that ANGPTL2 activated NLRP3 inflammasome via suppressing DUSP1 signaling, and NLRP3 knockdown abrogated the detrimental role of ANGPTL2 in aggravating LPS-induced cardiac inflammation. Furthermore, DUSP1 overexpression significantly inhibited ANGPTL2-mediated NLRP3 activation, and subsequently improved LPS-related cardiac dysfunction. In summary, ANGPTL2 exacerbated septic cardiomyopathy via activating NLRP3-mediated inflammation in a DUSP1-dependent manner, and our study uncovered a promising therapeutic target in preventing septic cardiomyopathy.

Keywords:  ANGPTL2; DUSP1; Heart failure; Inflammation; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2023.110701
Sci Total Environ. 2023 Aug 01. pii: S0048-9697(23)04578-3. [Epub ahead of print] 165953

Mechanistic illustration on lipid-metabolism disorders induced by triclosan exposure from the viewpoint of m6A-RNA epigenetic modification.

Shuya Chen, Xuedong Wang, Jin Yan, Zejun Wang, Qiuhui Qian, Huili Wang.

  As a typically anthropogenic contaminant, the toxicity effects of triclosan (TCS) were investigated in-depth from the viewpoint of m6A-pre-miRNAs modification. Based on miRNAs high-throughput sequencing, we unravelled the underlying molecular mechanisms regarding TCS-induced lipid-metabolism functional disorders. TCS exposure caused severe lipid accumulation in 120 hpf zebrafish liver and reduced their locomotor activity. Both bioinformatics analysis and experimental validation verified that TCS targeted miR-27b up-regulation to further trigger lipid-metabolism disorders and developmental malformations, including shortened body length, yolk cysts, curved spine and delayed yolk absorption. TCS exposure and miR-27b upregulation both caused the enhanced levels of triglyceride and total cholesterol. Knockdown and overexpression of miR-27b regulated the expression changes of several functional genes related to downstream lipid metabolism of miR-27b, and most downstream target genes of miR-27b were suppressed and enriched in the AMPK signaling pathway. The experiments of pathway inhibitors and agonists further evidenced that TCS caused lipid-metabolism disorders by suppressing the AMPK signaling pathway. In upstream of miR-27b, TCS decreased total m6A-RNA level by targeting upregulation of demethylase and downregulation of methylase reader ythdf1. Molecular docking and ythdf1 siRNA interference further confirmed that TCS targeted the expression change of ythdf1. Under ythdf1 knockdown in upstream of miR-27b, both abnormal lipid metabolism and miR-27b upregulation highlighted that TCS-induced lipid-metabolism disorders were attributable to the decreasing m6A-RNA methylation levels in vivo. These perspectives provide an innovative idea for prevention and treatment of the lipid metabolism-related diseases and these findings open a novel avene for TCS's risk assessment and early intervention of the contaminant.

Keywords:  Lipid-metabolism disorders; M(6)A-RNA epigenetic modification; Triclosan; miR-27 upregulation; ythdf1 knockdown

DOI:  https://doi.org/10.1016/j.scitotenv.2023.165953