Targeting YTHDF1 effectively re-sensitizes cisplatin-resistant colon cancer cells by modulating GLS-mediated glutamine metabolism DOI Creative Commons
Ping Chen,

Xi-qiao Liu,

Xiang Lin

et al.

Molecular Therapy — Oncolytics, Journal Year: 2021, Volume and Issue: 20, P. 228 - 239

Published: Jan. 18, 2021

Colorectal cancer (CRC) has a high mortality rate and poor prognosis. Despite chemotherapeutic agents such as cisplatin, which achieved better prognosis survival against cancer, drug resistance leads to significant challenges. Accumulating evidence suggests that YTHDF1, the N6-methyladenosine (m6A) "reader," is an important regulator in tumor progresses. Herein, we report YTHDF1 was significantly upregulated human colon tumors cell lines. Overexpression of decreased cisplatin sensitivity cells. From established cisplatin-resistant CRC line (LoVo CDDP R), detected Intriguingly, RNA sequencing (RNA-seq) results revealed glutamine metabolism enzymes were clearly LoVo R Glutamine uptake, is, glutaminase (GLS) activity, Furthermore, bioinformatics analysis indicated 3′ UTR GLS1 contained putative binding motif interaction further validated by protein-RNA assay (RNA immunoprecipitation [RIP]). demonstrated promoted protein synthesis GLS1. Inhibiting effectively synergizes with induce death. Finally, mediated through GLS1-glutamine axis vivo xenograft mouse model. In summary, our study reveals new mechanism for YTHDF1-promoted resistance, contributing overcoming chemoresistant cancers.

Language: Английский

The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation DOI Creative Commons
Liangyan Chen, Lian Wang,

Yue-Xiang Ren

et al.

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Nov. 23, 2020

Abstract Background Circular RNA (circRNAs) and hypoxia have been found to play the key roles in pathogenesis progression of cancer including colorectal (CRC). However, expressions functions specific circRNAs regulating hypoxia-involved CRC metastasis, that are relevant regulate HIF-1α levels remain elusive. Methods qRT-PCR was used detect expression mRNA cells tissues. Fluorescence situ hybridization (FISH) analyze location circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression knockdown cell lines vitro vivo, CCK8, colony formation, EdU assay, transwell, tumor growth metastasis models. Mechanistically, luciferase reporter western blots immunohistochemical stainings performed. Results Circ-Erbin highly expressed facilitated proliferation, migration vivo. Notably, circ-Erbin significantly promoted angiogenesis by increasing induced factor (HIF-1α) CRC. accelerated a cap-independent protein translation as sponges miR-125a-5p miR-138-5p, which synergistically targeted eukaryotic initiation 4E binding 1(4EBP-1). Conclusions Our findings uncover mechanism for mediated activation miR-125a-5p-5p/miR-138-5p/4EBP-1 axis is potential target treatment.

Language: Английский

Citations

154
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
Role of m6A writers, erasers and readers in cancer DOI Creative Commons
Zhen Fang,

Wentong Mei,

Chang Qu

et al.

Experimental Hematology and Oncology, Journal Year: 2022, Volume and Issue: 11(1)

Published: Aug. 9, 2022

Abstract The N(6)-methyladenosine (m6A) modification is the most pervasive of human RNAs. In recent years, an increasing number studies have suggested that m6A likely plays important roles in cancers. Many demonstrated involved biological functions cancer cells, such as proliferation, invasion, metastasis, and drug resistance. addition, closely related to prognosis patients. this review, we highlight advances understanding function various We emphasize importance progression look forward describe future research directions.

Language: Английский

Citations

148
Surmounting cancer drug resistance: New insights from the perspective of N6-methyladenosine RNA modification DOI
Bowen Li, Jingwen Jiang, Yehuda G. Assaraf

et al.

Drug Resistance Updates, Journal Year: 2020, Volume and Issue: 53, P. 100720 - 100720

Published: Aug. 20, 2020

Language: Английский

Citations

141
RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer DOI Creative Commons
Wei Li, Xiaolan Deng, Jianjun Chen

et al.

Seminars in Cancer Biology, Journal Year: 2022, Volume and Issue: 86, P. 664 - 677

Published: April 2, 2022

Language: Английский

Citations

85
YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner DOI Creative Commons
Hengyu Chen, Yuanhang Yu, Ming Yang

et al.

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: Feb. 23, 2022

N6-methyladenosine (m6A) is the most common post-transcriptional modification at RNA level. However, exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated. The integrating bioinformatics analyses were used screen clinical relevance dysregulated "reader" protein YTHDF1 from TCGA databases, which was further validated a cohort specimens. Furthermore, functional experiments such as CCK-8 assay, EdU wound healing transwell invasion assay cell cycle determine biological role cancer. RIP, m6A-IP, CLIP assays find target verification by RT-qPCR, western blot, polysome profiling assay. protein-protein interaction between FOXM1 detected via co-immunoprecipitation.Our study showed that overexpressed cells tissues At same time, high expression level positively correlated with tumor size, lymph node invasion, distant metastasis patients. depletion repressed proliferation, epithelial-mesenchymal transformation (EMT) induced G0/G1 phase arrest vitro vivo. We also demonstrated YTHDF1. Through recognizing binding m6A-modified mRNA FOXM1, accelerated translation process promoted metastasis. Whereas overexpression partially counteracted suppressed effects caused silence, verified regulatory relationship FOXM1.Our reveals novel YTHDF1/FOXM1 pathway contributes progression cancer, suggesting might applied potential biomarker therapeutic target. That advances our understanding tumorigenesis for regulation.

Language: Английский

Citations

78
The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma DOI Creative Commons

Lifang Ma,

Xiangfei Xue, Xiao Zhang

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Jan. 25, 2022

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Patient prognosis poor, and existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m6A) modification RNA has been suggested as a potential strategy to impede tumor progression. However, roles m6A in tumorigenesis unknown.Global levels expressions writers, erasers readers were evaluated by methylation assay, dot blot, immunoblotting, immunohistochemistry ELISA human LUAD, mouse models cell lines. Cell viability, 3D-spheroid generation, vivo formation, experiments cell- patient-derived xenograft mice survival analysis conducted explore impact on LUAD. The RNA-protein interactions, translation, putative sites glycolysis explored investigation mechanism underlying how stimulates tumorigenesis.The elevation global level specimens resulted combined upregulation writer methyltransferase 3 (METTL3) downregulation eraser alkB homolog 5 (ALKBH5). Elevated was associated with poor overall patients. Reducing knocking out METTL3 overexpressing ALKBH5 suppressed generation cells intra-pulmonary formation mice. Mechanistically, m6A-dependent stimulation occurred via enolase 1 (ENO1). ENO1 mRNA methylated at 359 A, which facilitated it's binding reader YTH protein (YTHDF1) enhanced translation ENO1. positively correlated levels, negatively In addition, preclinical models, tumors higher showed more sensitive response inhibition pan-methylation, ENO activity LUAD.The least partially orchestrated METTL3, ALKBH5, YTHDF1-mediated translation. Blocking this may represent treatment

Language: Английский

Citations

72
The structure and function of YTHDF epitranscriptomic m6A readers DOI Creative Commons
Vilbert Sikorski, Simona Selberg, Maciej Łałowski

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(6), P. 335 - 353

Published: April 15, 2023

Specific RNA sequences modified by a methylated adenosine, N6-methyladenosine (m6A), contribute to the post-transcriptional regulation of gene expression. The quantity m6A in is orchestrated enzymes that write and erase it, while its effects are mediated proteins bind read this modification. Dysfunction regulatory process has been linked human disease. Although initial focus on pharmacological targeting writer eraser enzymes, interest reader challenged lack clear understanding their functional roles molecular mechanisms action. Readers m6A-modified (m6A-RNA) – YTH (YT521-B homology) domain-containing protein family paralogs 1–3 (YTHDF1–3, referred here as DF1–DF3) emerging therapeutic targets links pathological processes such cancer inflammation regulating m6A-RNA fate become clear. We provide an updated modes action DF1–DF3 review structures unlock insights into drug design approaches for DF paralog-selective inhibition.

Language: Английский

Citations

55
N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms DOI Creative Commons
Lin Chen, Yang Gao, Simiao Xu

et al.

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

Published: March 14, 2023

As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m 6 A) is involved a wide range of physiological pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, YTHDF3, are class cytoplasmic m A-binding defined by vertebrate YTH domain, exert extensive functions regulating RNA destiny. Distinct expression patterns YTHDF specific cell types or developmental stages result prominent differences multiple biological processes, such as embryonic development, stem fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, tumorigenesis. mediates tumor proliferation, metastasis, drug resistance, possesses potential predictive therapeutic biomarkers. Here, we mainly summary structures, roles, mechanisms especially cancers, well their current limitations future considerations. This will provide novel angles for deciphering A regulation system.

Language: Английский

Citations

51
The role of RNA methylation in tumor immunity and its potential in immunotherapy DOI Creative Commons
Yan Li,

Haoer Jin,

Qingling Li

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 20, 2024

Abstract RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of methylation on tumor immunity. The primary types encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), 3-methylcytidine (m3C). Compelling evidence underscores involvement regulating microenvironment (TME). By affecting translation stability through "writers", "erasers" "readers", influence dysregulation immune cells factors. Consequently, plays pivotal role immunity mediating various behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed mechanisms several methylations, providing comprehensive overview their roles underlying within among immunocytes. exploring how these modifications mediate evasion, also examine potential applications immunotherapy. This review aims to provide novel insights strategies for identifying targets advancing cancer immunotherapy efficacy.

Language: Английский

Citations

32