Identification of potent allosteric inhibitors of PRMT3: pharmacophore based 3D-QSAR modeling and molecular simulations approach DOI Creative Commons

Shoufia Jabeen Mubarak,

Hemamalini Vedagiri

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 8, 2023

Abstract Protein arginine methyltransferases are a family of proteins that play an important role in the regulation gene expression, mainly involved epigenetic modifications like DNA methylation and histone acetylation. methyltransferase 3 (PRMT) is member PRMT enzymes various cellular processes, including transcriptional regulation, RNA processing, signal transduction. PRMT3 levels considerably enhanced certain types cancers particularly breast, colorectal, lung ovarian cancers. Studies have indicated promotes tumor growth by activating oncogenes suppressing suppressor genes. histone-modifying enzyme catalyzes transfer methyl groups from S-adenosylmethionine (SAM) to specific residues target proteins, thereby modulating their function. However, activity not only regulated its catalytic domain but also allosteric mechanisms control enzymatic activity. Furthermore, targeting could potentially serve as therapeutic strategy for treating cancer. This study focuses on exploring diverse compound libraries identify potential inhibitors would modify computational approach involves generation pharmacophore hypothesis with 3D-QSAR validation, followed virtual screening, docking dynamic simulations potent bioactive compounds inhibitors. Virtual screening natural products revealed top lead molecules cladribine, capecitabine, gefitinib, D175-0195, F602-1150 F1361-0042. further validation studies warranted confirm these findings.

Language: Английский

PRMT3‐Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma DOI Creative Commons
Yiru Wang, Can Wang,

Xue Guan

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(36)

Published: Nov. 16, 2023

Abstract Protein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms the treatment sensitivity of endometrial cancer (EC) remain unclear warrant further investigation. Here, a comprehensive analysis Cancer Genome Atlas database Clinical Proteomic Tumor Analysis Consortium identifies that PRMT3 an important role EC. Specifically, experiments show inhibition enhances susceptibility EC cells to ferroptosis. Mechanistically, interacts with Methyltransferase 14 (METTL14) is involved methylation. In addition, inhibition‐mediated METTL14 overexpression promotes methylation modification via m 6 A‐YTHDF2‐dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, accelerating Notably, combined blockade anti‐PD‐1 therapy display more potent antitumor effects by ferroptosis cell‐derived xenograft models. The specific inhibitor SGC707 exerts same immunotherapeutic sensitizing effect patient‐derived model. blocking improves suppression response cisplatin radiation therapy. Altogether, this work demonstrates depletion promising target for

Language: Английский

Citations

34
Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance DOI Creative Commons
Yongxia Zhu, Tong Xia,

D Chen

et al.

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 72, P. 101016 - 101016

Published: Nov. 3, 2023

Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic methylation, which regulates various biological and pathological processes, as result, they attractive therapeutic targets overcoming anti-cancer drug resistance. The ongoing small molecules targeting PRMTs has resulted generation chemical probes modulating most facilitated clinical treatment advanced oncology targets, including PRMT1 PRMT5. In this review, we summarize mechanisms underlying protein methylation roles specific driving Furthermore, highlight potential implications PRMT inhibitors decreasing promote formation maintenance drug-tolerant cells via several mechanisms, altered efflux transporters, autophagy, DNA damage repair, stem cell-related function, epithelial-mesenchymal transition, disordered tumor microenvironment. Multiple preclinical trials have demonstrated that inhibitors, particularly PRMT5 can sensitize drugs, chemotherapeutic, targeted therapeutic, immunotherapeutic agents. Combining with existing will be promising approach enhanced knowledge complex functions guide future may help identify new indications.

Language: Английский

Citations

25
The functions and mechanisms of post-translational modification in protein regulators of RNA methylation: Current status and future perspectives DOI
Youming Chen,

Zuli Jiang,

Ying Yang

et al.

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 253, P. 126773 - 126773

Published: Sept. 9, 2023

Language: Английский

Citations

23
Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia DOI
Song Fan,

Chen Hou,

Sen Zhao

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: 120, P. 111228 - 111228

Published: May 13, 2024

Language: Английский

Citations

9
LncRNAs and the Cancer Epigenome: Mechanisms and Therapeutic Potential DOI
Revathy Nadhan, Ciro Isidoro, Yong Sang Song

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 605, P. 217297 - 217297

Published: Oct. 16, 2024

Language: Английский

Citations

5
PRMT3 Gene Expression and Methylation Levels in Arrested Embryos: Implications for Developmental Arrest Defects DOI
Wuwen Zhang, Shifeng Li, Kai Li

et al.

Developmental Biology, Journal Year: 2025, Volume and Issue: 520, P. 264 - 271

Published: Jan. 31, 2025

Language: Английский

Citations

0
Unlocking the brain's code: The crucial role of post-translational modifications in neurodevelopment and neurological function DOI
Peng Ye,

Wangzheqi Zhang,

Yan Liao

et al.

Physics of Life Reviews, Journal Year: 2025, Volume and Issue: 53, P. 187 - 214

Published: March 23, 2025

Language: Английский

Citations

0
Contributions of Low-frequency-mutated Genes in Pancreatic Tumorigenesis and Their Implications in Precision Cancer Therapy DOI Creative Commons
Shih‐Han Hsu, Tzu-Lei Kuo, Ming‐Chuan Hsu

et al.

Journal of Cancer Research and Practice, Journal Year: 2025, Volume and Issue: 12(1), P. 1 - 5

Published: Jan. 1, 2025

Abstract Pancreatic cancer is an aggressive malignancy, and the limited treatment options contribute to its high mortality rate. In 2023, it ranked as seventh leading cause of cancer-related deaths in Taiwan, with similar incidence rates highlighting need for novel therapies. Recent next-generation sequencing studies have identified highly variable (or high-frequency mutation) genes pancreatic cells, including KRAS , TP53 CDKN2A SMAD4 . Several defective or low-frequency-mutated also been tumor tissues; however, their roles contributions tumorigenesis remain poorly characterized. Furthermore, remains unclear whether patients harboring these are susceptible specific targeted therapies combination treatments. This study focuses on understanding potential therapeutic targets. this study, we review relevant published by our groups past 5 years. Using various molecular genetic approaches, oncogenic/tumor-suppressive several tumorigenesis. These findings support development precision targeting alterations cancer. Identifying actionable targets provides a basis creating tailored treatments improve survival outcomes.

Language: Английский

Citations

0
Regulation of protein arginine methyltransferase in osteoporosis: a narrative review DOI Creative Commons
Ruiming Wen, Ruiqi Huang, Mingbo Yang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: April 24, 2025

Osteoporosis (OP), a systemic bone disease characterised by increased fragility and susceptibility to fracture, is mainly caused decline in mineral density (BMD) quality an imbalance between formation resorption. Protein arginine methyltransferases (PRMTs) are epigenetic factors post-translational modification (PTM) enzymes participating various biological processes, including mRNA splicing, DNA damage repair, transcriptional regulation, cell signalling. They act catalysing the transfer of residues and, thus, have become therapeutic targets for OP. In-depth studies found that these also play key roles matrix protein metabolism, skeletal proliferation differentiation, signal pathway regulation regulate formation, resorption balance, or both jointly maintain health stability. However, expression changes mechanisms action multiple members PRMT family differ Therefore, this paper discusses functions, action, influencing PRMTs OP, which expected provide new understanding pathogenesis Furthermore, we present theoretical support development more precise effective treatment strategies as well further study molecular PRMTs.

Language: Английский

Citations

0
PRMT3‐Mediated H4R3me2a Promotes Primary Age‐Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron DOI Creative Commons
Haotian Liu,

Xinnan Liu,

Fengyuan Tian

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

Abstract Primary age‐related tauopathy (PART) and Alzheimer's disease (AD) both exhibit 3R/4R hyperphosphorylated tau‐positive neurofibrillary tangles (NFTs) within the hippocampal–entorhinal system. Notably, PART patients show a higher degree of tau hyperphosphorylation in entorhinal cortex (EC) than AD, yet molecular mechanisms driving Aβ‐independent remain poorly understood. Herein, through transcriptomic profiling postmortem EC tissues vitro vivo functional validation, present study identifies protein arginine methyltransferase 3 (PRMT3) as critical driver hyperphosphorylation. Mechanistically, PRMT3‐mediated is dependent on asymmetric dimethylation histone H4 at (H4R3me2a), which upregulates miR‐448. Elevated miR‐448 specifically targets suppresses IGF1R, leading to downstream GSK3β activation subsequent PI3K/AKT/GSK3β signaling. Treatment with SGC707, selective PRMT3 inhibitor, effectively reduces demonstrates therapeutic promise for potentially other tauopathies. Collectively, this defines PRMT3/H4R3me2a/miR‐448 axis regulatory pathway PART, underscoring potential inhibition targeted strategy

Language: Английский

Citations

0