Engineered Methionine Adenosyltransferase Cascades for Metabolic Labeling of Individual DNA Methylomes in Live Cells DOI Creative Commons

Liepa Gasiulė,

Vaidotas Stankevičius, Kotryna Kvederavičiūtė

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(27), P. 18722 - 18729

Published: June 29, 2024

Methylation, a widely occurring natural modification serving diverse regulatory and structural functions, is carried out by myriad of S-adenosyl-l-methionine (AdoMet)-dependent methyltransferases (MTases). The AdoMet cofactor produced from l-methionine (Met) ATP family multimeric methionine adenosyltransferases (MAT). To advance mechanistic functional studies, strategies for repurposing the MAT MTase reactions to accept extended versions transferable group corresponding precursors have been exploited. Here, we used structure-guided engineering mouse MAT2A enable biocatalytic production an analogue, Ado-6-azide, synthetic S-(6-azidohex-2-ynyl)-l-homocysteine (N3-Met). Three engineered variants showed catalytic proficiency with analogues supported DNA derivatization in cascade M.TaqI variant DNMT1 both absence presence competing Met. We then installed two as MAT2A-DNMT1 cascades embryonic stem cells using CRISPR-Cas genome editing. resulting cell lines maintained normal viability methylation levels Dnmt1-dependent azide tags upon exposure N3-Met physiological This first time demonstrates genetically stable system biosynthetic which enables mild metabolic labeling DNMT-specific methylome live mammalian cells.

Language: Английский

The hallmarks of cancer immune evasion DOI
Claudia Galassi, Timothy A. Chan, Ilio Vitale

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1825 - 1863

Published: Oct. 10, 2024

Language: Английский

Citations

78
Amino acid metabolism in tumor biology and therapy DOI Creative Commons
Jie Chen,

Likun Cui,

Shaoteng Lu

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 13, 2024

Abstract Amino acid metabolism plays important roles in tumor biology and therapy. Accumulating evidence has shown that amino acids contribute to tumorigenesis immunity by acting as nutrients, signaling molecules, could also regulate gene transcription epigenetic modification. Therefore, targeting will provide new ideas for treatment become an therapeutic approach after surgery, radiotherapy, chemotherapy. In this review, we systematically summarize the recent progress of malignancy their interaction with signal pathways well effect on microenvironment Collectively, highlight potential application future expectation.

Language: Английский

Citations

68
New frontiers in the cGAS-STING intracellular DNA-sensing pathway DOI Creative Commons

Steve Dvorkin,

Stephanie Cambier,

Hannah E. Volkman

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 718 - 730

Published: April 1, 2024

Language: Английский

Citations

67
Cancer cell metabolism and antitumour immunity DOI
Mara De Martino, Jeffrey C. Rathmell, Lorenzo Galluzzi

et al.

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: 24(9), P. 654 - 669

Published: April 22, 2024

Language: Английский

Citations

58
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer DOI
Fuming Li, Pingyu Liu, Mi Wen

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(1), P. 131 - 146

Published: Jan. 2, 2024

Language: Английский

Citations

29
cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors DOI Creative Commons

Guohao Li,

Xiangqian Zhao,

Zuda Zheng

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 21, 2024

Abstract Type I interferons (IFN-I) play pivotal roles in tumor therapy for three decades, underscoring the critical importance of maintaining integrity IFN-1 signaling pathway radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, specific mechanism by which IFN-I contributes to these therapies, particularly terms activating dendritic cells (DCs), remains unclear. Based on recent studies, aberrant DNA cytoplasm activates cyclic GMP-AMP synthase (cGAS)- stimulator interferon genes (STING) pathway, turn produces IFN-I, is essential antiviral anticancer immunity. Notably, STING can also enhance immunity promoting autophagy, inflammation, glycolysis an IFN-I-independent manner. These research advancements contribute our comprehension distinctions between drugs agonists context oncology shed light challenges involved developing agonist drugs. Thus, we aimed summarize novel mechanisms underlying cGAS-STING-IFN-I signal activation DC-mediated antigen presentation its role cancer immune cycle this review.

Language: Английский

Citations

21
The potential of methioninase for cancer treatment DOI
Louay Abo Qoura, Konstantin V. Balakin, Robert M. Hoffman

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189122 - 189122

Published: May 23, 2024

Language: Английский

Citations

16
Targeting methionine metabolism in cancer: opportunities and challenges DOI
Peng Bin, Chuanlong Wang, Hangchao Zhang

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(5), P. 395 - 405

Published: April 5, 2024

Language: Английский

Citations

15
Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis DOI
Ming Kong, Junjing Zhou,

Aoqi Kang

et al.

Gut, Journal Year: 2024, Volume and Issue: 73(5), P. 810 - 824

Published: Jan. 4, 2024

Objective Liver fibrosis is a prelude to host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from quiescent state myofibroblasts, are the major source for excessive production extracellular matrix proteins. In present study, we investigated role Suv39h1, lysine methyltransferase, in HSC-myofibroblast transition and implication fibrosis. Design HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding f/f mice Lrat -Cre Postn ERT2 mice. induced CCl 4 injection bile duct ligation. Results We report that expression universally upregulated during different cell animal models human cirrhotic tissues. Consistently, knockdown blocked vitro. ameliorated More importantly, inhibition small-molecule compound chaetocin dampened culture mitigated Mechanistically, bound promoter heme oxygenase 1 (HMOX1) repressed HMOX1 transcription. depletion blunted effects on vitro vivo. Transcriptomic analysis revealed might contribute modulating retinol homeostasis. Finally, overexpression attenuated both preventive scheme therapeutic scheme. Conclusions Our data demonstrate previously unrecognised offer proof-of-concept its targetability intervention cirrhosis.

Language: Английский

Citations

13
Salmonella-mediated methionine deprivation drives immune activation and enhances immune checkpoint blockade therapy in melanoma DOI Creative Commons
Sujin Zhou, Shiwei Zhang, Kexin Zheng

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(2), P. e008238 - e008238

Published: Feb. 1, 2024

Background Although immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it crucial to identify effective drug combinations develop new therapies the treatment of melanoma. SGN1, a genetically modified Salmonella typhimurium species that causes targeted deprivation methionine in tumor tissues, currently under investigation clinical trials. However, inhibitory effect SGN1 on melanoma benefits combination ICIs remain largely unexplored. Therefore, this study aims investigate antitumor potential its ability enhance efficacy antibody-based programmed cell death-ligand 1 (PD-L1) inhibitors murine Methods The activity PD-L1 was studied through models. Further, Cancer Genome Atlas-melanoma cohort clustered using ConsensusClusterPlus based deprivation-related genes, characterization performed xCell, Microenvironment Cell Populations-counter, Estimation Stromal Immune cells MAlignant Tumor tissues Expression data, immunophenoscore (IPS) analyses. messenger RNA data death-1 (PD-1) immunotherapy response were obtained from Gene Omnibus database. Set Enrichment Analysis deprivation-up gene set determine differences between pretreatment responders non-responders. Results This showed both, intratumoral intravenous administration subcutaneous B16-F10 melanomas, suppress growth, which associated an activated CD8+T-cell microenvironment. Combination systemic anti-PD-L1 resulted better than individual monotherapies, respectively, high therapeutic increase level tumor-specific CD8 + T cells. Two clusters consisting genes identified. Patients cluster 2 had higher expression methionine_deprivation_up outcomes, infiltration levels compared 1. Western blot, IPS analysis, revealed deficiency may show ICI Conclusions： reports -based as potent anticancer agent against lays groundwork synergistic brought about by improving microenvironment melanomas.

Language: Английский

Citations

11