PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

Tang, Yuling; Dong, Lei; Zhang, Chong; Li, Xiubin; Li, Rongyu; Lin, Huisang; Qi, Yini; Tang, Mingchuan; Peng, Yanli; Liu, Chuan; Zhou, Jian; Hou, Ning; Liu, Wenjia; Guan, Yang; Teng, Yan

doi:10.7150/ijbs.71581

Cited by 9 publications

(3 citation statements)

References 77 publications

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“…Unlike trimethylation on lysine, which usually presents the start of transcription process, the effect of dimethylation is more flexible, including both activation and suppression functions on different histones [ 42 ]. Therefore, the aberrant expression of PRMT5 leads to different results for different types of cells and the employment of PRMT5 inhibitors may have a selective effect [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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“…Gr1 + staining was quantified using Image J software. TUNEL staining was conducted through a TUNEL Assay Kit (#C10617, Invitrogen) 25 .…”

Section: Methodsmentioning

confidence: 99%

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Zhu¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3 -/- ) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

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“…These PRMT family members can regulate the expression of tumor-associated genes, thereby promoting tumor cell proliferation, migration, and invasion. On the other hand, some studies have also found that the expression levels of PRMT2 and PRMT5 are down-regulated in tumors, and their functions are associated with inhibition of tumor cell proliferation and invasion [15,16]. This suggests that different PRMT family members may have different roles in tumors.…”

Section: Introductionmentioning

confidence: 99%

Identification of protein methyltransferases 5 associated with ferroptosis and immune cell infiltration of head and neck squamous cell carcinoma

Zhang,

Liu,

Wang

et al. 2024

Aging

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Head and neck tumors are malignant tumors that appear in the head and neck. Although much progress has been made in the treatment of head and neck tumors, many challenges remain. The prognosis of some advanced cases remains poor and survival and quality of life after treatment face certain limitations. Therefore, further research into the pathogenesis and treatment options for head and neck tumors is important in order to improve the prognosis and quality of life of patients. The Protein Arginine Methyltransferase (PRMT) family is a class of enzymes that are responsible for adding methyl groups to arginine residues in proteins. PRMT family members play important roles in regulating many cellular processes, such as transcriptional regulation, signaling, and cell cycle regulation. Recent studies have shown that the PRMT family also plays an important function in tumorigenesis and development. Here, we found that PRMT family members are significantly overexpressed in head and neck tumors and that PRMT5 may serve as an independent prognostic factor in head and neck tumors. We found that PRMT5-regulated differential genes were significantly enriched in tumorassociated signaling pathways such as IL-17 and p53. And we also found that the expression of PRMT5 in head and neck tumors was significantly correlated with immune cell infiltration, m6A as well as the expression of ferroptosis-related genes, and drug sensitivity. These results suggest that PRMT may play an important role in the development of head and neck tumors.

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PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

Cited by 9 publications

References 77 publications

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Identification of protein methyltransferases 5 associated with ferroptosis and immune cell infiltration of head and neck squamous cell carcinoma

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