Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination DOI Creative Commons
Zhijia Sun,

Haixing Mai,

Chunyuan Xue

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(12), P. e007415 - e007415

Published: Dec. 1, 2023

Background Limited response to programmed death ligand-1 (PD-L1)/programmed 1 (PD-1) immunotherapy is a major hindrance of checkpoint in non-small cell lung cancer (NSCLC). The abundance PD-L1 on the tumor surface crucial for responsiveness PD-1/PD-L1 immunotherapy. However, negative control expression and physiological significance inhibition NSCLC remain obscure. Methods Bioinformatics analysis was performed profile investigate long non-coding RNAs that negatively correlated with positively CD8+T infiltration NSCLC. Immunofluorescence, vitro PD-1 binding assay, T cell-induced apoptosis assays vivo syngeneic mouse models were used functional roles LINC02418 mmu-4930573I07Rik regulating anti-PD-L1 therapeutic efficacy molecular mechanism LINC02418-enhanced downregulation explored by immunoprecipitation, RNA immunoprecipitation (RIP), ubiquitination assays. RIP, luciferase reporter, messenger degradation m6A modification or expression. immunohistochemistry (IHC) verification determine LINC02418, infiltration. Results regulator infiltration, predicting favorable clinical outcomes patients downregulates enhancing mediated E3 ligase Trim21. Both hsa-LINC02418 (its homologous mice) regulate via Trim21, inducing . Furthermore, METTL3 N6-methyladenosine (m6A) YTHDF2 reader upregulates mmu-4930573I07Rik. In NSCLC, inversely Conclusion functions as cells promoting through ubiquitin-proteasome pathway. regulated METTL3/YTHDF2-mediated modification. This study illuminates underlying mechanisms regulation presents promising target improving effectiveness therapy

Language: Английский

RNA modifications: importance in immune cell biology and related diseases DOI Creative Commons
Lian Cui, Rui Ma,

Jiangluyi Cai

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Language: Английский

Citations

205
Targeting the RNA m6A modification for cancer immunotherapy DOI Creative Commons
Xinxin Li, Shoubao Ma, Youcai Deng

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: March 16, 2022

Abstract N 6 -methyladenosine (m A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription translation programs that promote cancer occurrence progression. Although defective gene regulation resulting from m A often affects oncogenic tumor-suppressing networks, can also modulate tumor immunogenicity immune cells involved in anti-tumor responses. Understanding this counterintuitive concept aid design new drugs target to potentially improve outcomes immunotherapies. Here, we provide an up-to-date comprehensive overview how modifications intrinsically affect alterations cell extrinsically responses microenvironment (TME). We review strategies for modulating endogenous immunity discuss challenge reshaping TME. Strategies include: combining specific efficient inhibitors against regulators with checkpoint blockers; generating effective programmable gene-editing system enables manipulation individual sites; establishing enhance T or natural killer cells; using nanoparticles specifically tumor-associated macrophages (TAMs) deliver messenger RNA small interfering A-related molecules repolarize TAMs, enabling them remodel The goal help field understand shape TME so better immunotherapy be designed developed.

Language: Английский

Citations

151
The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability DOI Creative Commons
Nan Zhang, Yan Shen, Huan Li

et al.

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(2), P. 194 - 205

Published: Feb. 1, 2022

Abstract N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role initiation progression diseases such as cancer. Here, we identified IGF2BP3 specifically overexpressed acute myeloid leukemia (AML), subtype associated with poor prognosis high genetic risk. required for maintaining AML cell survival an m6A-dependent manner, knockdown dramatically suppresses apoptosis, reduces proliferation, impairs leukemic capacity cells vitro vivo. Mechanistically, interacts RCC2 stabilizes expression m6A-modified RNA. Thus, provided compelling demonstrating reader contributes to tumorigenesis can serve target development cancer therapeutics.

Language: Английский

Citations

84
Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance DOI Creative Commons
Hong Lin, Di Wang, Pinghan Wang

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: July 18, 2022

Abstract The resistance of tumor cells to therapy severely impairs the efficacy treatment, leading recurrence and metastasis various cancers. Clarifying underlying mechanisms therapeutic may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is most prevalent RNA modification in eukaryotes, involved regulation splicing, translation, transport, degradation, stability processing, thus affecting several physiological processes progression. As a novel type multifunctional non-coding RNAs (ncRNAs), circular (circRNAs) have been demonstrated play vital roles anticancer therapy. Currently, accumulating studies revealed mutual m6A circRNAs, their interaction can further influence sensitivity treatment. In this review, we mainly summarized recent advances circRNAs modulation resistance, as well interplay potential mechanisms, providing promising insights future directions reversal cancer.

Language: Английский

Citations

84
New insight into circRNAs: characterization, strategies, and biomedical applications DOI Creative Commons

Xin-Yi Feng,

Shun-Xin Zhu,

Ke‐Jia Pu

et al.

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Oct. 12, 2023

Abstract Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput sequencing and experimental technologies have enabled the extensive identification characterization circRNAs, such as novel types biogenesis, tissue-specific cell-specific expression patterns, epigenetic regulation, translation potential, localization metabolism. Increasing evidence has revealed that participate in diverse cellular processes, their dysregulation is involved pathogenesis various diseases, particularly cancer. In this review, we systematically discuss databases, challenges for circRNA discovery, new insight into strategies used studies biomedical applications. Although recent advanced understanding knowledge approaches annotation, functional applications continuously needed to provide insights circRNAs. The emergence circRNA-based protein strategy will be promising direction field biomedicine.

Language: Английский

Citations

53
Betaine alleviates cognitive impairment induced by homocysteine through attenuating NLRP3-mediated microglial pyroptosis in an m6A-YTHDF2-dependent manner DOI Creative Commons
Zhijun Yang, Siyu Huang, Kaiyi Zhong

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 69, P. 103026 - 103026

Published: Jan. 4, 2024

Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves methyl donor and plays role reducing Hcy. However, effects mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected Hcy (400 μg/kg) through vena caudalis, (2.5 % w/v) was supplemented via drinking water for 14 days. supplementation could attenuate Y maze novel object recognition tests by repairing brain injury. Meanwhile, microglial activation observed to be inhibited using immunofluorescence sholl analysis. Secondly, HMC3 cells treated betaine, which found decrease ROS level, ameliorate cell membrane rupture, reduce release LDH, IL-18 IL-1β, damage microglia neurons. Mechanistically, alleviates inhibiting pyroptosis expressions NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-1β. treatment can increase SAM/SAH ratio, confirming its enhancement methylation capacity. Furthermore, enhance N6-methyladenosine (m6A) modification NLRP3 mRNA, reduced mRNA stability increasing expression m6A reader YTH RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 reverse inhibitory effect pyroptosis. Our data demonstrated that attenuated suppressing NLRP3/caspase-1/GSDMD pathway m6A-YTHDF2-dependent manner.

Language: Английский

Citations

21
METTL3 protects METTL14 from STUB1‐mediated degradation to maintain m6A homeostasis DOI Open Access

Zhan‐Cheng Zeng,

Qi Pan,

Yu‐Meng Sun

et al.

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(3)

Published: Jan. 4, 2023

Language: Английский

Citations

33
METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression DOI Creative Commons
Wei Wei, Zhongyuan Zhang, Bin Shi

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: June 20, 2023

Abstract Background Glycolysis is the key hallmark of cancer and maintains malignant tumor initiation progression. The role N6-methyladenosine (m6A) modification in glycolysis largely unknown. This study explored biological function m6A methyltransferase METTL16 glycolytic metabolism revealed a new mechanism for progression Colorectal (CRC). Methods expression prognostic value was evaluated using bioinformatics immunohistochemistry (IHC) assays. functions CRC analyzed vivo vitro. Glycolytic assays were used to verify Suppressor glucose by autophagy (SOGA1). protein/RNA stability, RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) pull-down explore potential molecular mechanisms. Results SOGA1 direct downstream target involved mediated significantly enhances mRNA stability via binding “reader” protein insulin-like growth factor 2 1 (IGF2BP1). Subsequently, promotes AMP-activated kinase (AMPK) complex ubiquitination, inhibits its phosphorylation, thus upregulates pyruvate dehydrogenase 4 (PDK4), crucial controlling metabolism. Moreover, Yin Yang (YY1) can transcriptionally inhibit cells directly promoter. Clinical data showed that positively correlated PDK4, associated with poor prognosis patients. Conclusions Our findings suggest METTL16/SOGA1/PDK4 axis might be promising therapeutic targets CRC.

Language: Английский

Citations

31
ALKBH5/YTHDF2‐mediated m6A modification of circAFF2 enhances radiosensitivity of colorectal cancer by inhibiting Cullin neddylation DOI Creative Commons
Yingjie Shao, Zhenhua Liu, Xing Song

et al.

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(7)

Published: June 28, 2023

Abstract Background Circular RNA (circRNA) and N6‐methyladenosine (m6A) play a critical role in tumour occurrence development, including colorectal cancer (CRC). However, little is known about the interaction between circRNA m6A radiosensitivity of CRC. Here, we investigated novel m6A‐regulated Methods Differentially expressed circRNAs from radiosensitive radioresistant CRC tissues were screened. Modifications selected examined by methylated immunoprecipitation assay. Finally, subjected to Results We identified that circAFF2 closely related both CircAFF2 was highly patients with rectal cancer, high expression had better prognosis. In addition, can enhance cells vitro vivo. The regulation involves ALKBH5‐mediated demethylation, followed its recognition degradation via YTHDF2. Rescue experiments revealed could reverse induced ALKBH5 or Mechanistically, binds CAND1, promotes binding CAND1 Cullin1 inhibits neddylation, subsequently impacting Conclusion characterised as m6A‐modified validated ALKBH5/YTHDF2/circAFF2/Cullin‐NEDD8 axis potential radiotherapy target for

Language: Английский

Citations

31
Metabonomic analysis of follicular fluid in patients with diminished ovarian reserve DOI Creative Commons
Jianan Li, Zhourui Zhang, Yiqiu Wei

et al.

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 27, 2023

Background Ovarian reserve is an important factor determining female reproductive potential. The number and quality of oocytes in patients with diminished ovarian (DOR) are reduced, even if vitro fertilization-embryo transfer (IVF-ET) used to assist their pregnancy, the clinical pregnancy rate live birth still low. Infertility caused by reduced one most difficult problems field reproduction. Follicular fluid microenvironment for oocyte survival, metabolic characteristics follicular can be obtained metabolomics technology. By analyzing status fluid, we hope find factors that affect new diagnostic markers provide clues early detection intervention DOR. Methods In this research, 26 infertile women DOR 28 volunteers normal receiving IVF/ET were recruited, samples collected a nontargeted metabonomic study. orthogonal partial least squares discriminant analysis model was understand separation trend two groups, KEGG analyze possible pathways involved differential metabolites, random forest algorithm establish model. Results 12 upregulated 32 downregulated metabolites detected analysis, mainly including amino acids, indoles, nucleosides, organic steroids, phospholipids, fatty acyls, oxygen compounds. Through these aminoacyl-tRNA biosynthesis, tryptophan metabolism, pantothenate CoA purine metabolism. AUC value based on top 10 0.9936. Conclusion shows unique characteristics. These data us rich biochemical information research basis exploring pathogenesis predicting function.

Language: Английский

Citations

30