PRMT5-activated c-Myc promote bladder cancer proliferation and invasion through up-regulating NF-κB pathway

Zhang, Liang; Shao, Guangfeng; Shao, Jianhui; Zhao, Jie

doi:10.1016/j.tice.2022.101788

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…Although the FKA-PRMT5 binding mode was similar to the EPZ015666-PRMT5 binding mode, the binding sites for FKA on PRMT5 were Y304 and F580, which presented strong hydrogen bond interaction [ 11 ]. Y304 had been proven to be a direct site where PRMT5 can catalyze the substrate peptide and can be phosphorylated by JAK2.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it could strongly affect the binding of PRMT5 to H2A and H4 [ 45 , 46 ]. F580, a predominant binding site for EPZ015666, also affected PRMT5 binding with the substrate peptide [ 11 ]. By targeting Y304 and F580, we found that FKA affected the symmetrical arginine dimethylation levels of H2A and H4.…”

Section: Discussionmentioning

confidence: 99%

“…Most PRMTs have been implicated in the regulation of cancer-associated epigenetics and chromatin transcription signaling, RNA metabolism, and DNA repair [ 10 ]. Recent reports have shown that some PRMTs play indispensable roles in regulating BC and are closely related to the proliferation, invasion, and poor prognosis of the disease [ 11 ]. However, no systematic analysis on PRMTs in BC has been performed to date, and the type of PRMT that specifically promotes the development of BC remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…PRMT5 has been reported to promote c-Myc expression and consequently up-regulate the NF-κB pathway ( 43 ). Furthermore, PRMT5 has been shown to stabilise c-Myc in pancreatic cancer cells ( 41 ).…”

Section: Prmt5 Activity and Cancermentioning

confidence: 99%

The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality

Bray,

Balcells,

McNeish

et al. 2023

Front. Oncol.

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Approximately 15% of cancers exhibit loss of the chromosomal locus 9p21.3 – the genomic location of the tumour suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). A loss of MTAP increases the pool of its substrate methylthioadenosine (MTA), which binds to and inhibits activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 utilises the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues of protein substrates and regulate their activity, notably histones to regulate transcription. Recently, targeting PRMT5, or MAT2A that impacts PRMT5 activity by producing SAM, has shown promise as a therapeutic strategy in oncology, generating synthetic lethality in MTAP-negative cancers. However, clinical development of PRMT5 and MAT2A inhibitors has been challenging and highlights the need for further understanding of the downstream mediators of drug effects. Here, we discuss the rationale and methods for targeting the MAT2A/PRMT5 axis for cancer therapy. We evaluate the current limitations in our understanding of the mechanism of MAT2A/PRMT5 inhibitors and identify the challenges that must be addressed to maximise the potential of these drugs. In addition, we review the current literature defining downstream effectors of PRMT5 activity that could determine sensitivity to MAT2A/PRMT5 inhibition and therefore present a rationale for novel combination therapies that may not rely on synthetic lethality with MTAP loss.

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“…Reports have shown that some PRMTs are essential for the regulation of BC and are closely associated with its proliferation, invasion, and poor prognosis. 10 . Further, PRMT5 has been identi ed as an epigenetic therapeutic target for bladder cancer, and FKA can be used as a targeted inhibitor of PRMT5 11 .…”

Section: Introduction Page 4/22mentioning

confidence: 99%

Identification of molecular subtypes based on histone arginine methylation in bladder cancer

Guo

Liang

et al. 2023

Preprint

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Background Histone arginine methylation is an important feature in bladder cancer that affects prognosis and therapeutic response. However, the investigation of molecular subtypes based upon histone arginine methylation is still being exploited. Methods From the TCGA database, we obtained the RNA sequencing and somatic mutation results of 412 bladder cancer patients. To identify molecular subtypes associated with histone arginine methylation, consensus clustering was performed. These histone arginine methylation-associated subtypes were compared in terms of prognosis, clinical features, immune cell infiltration, and somatic mutation profiles. Moreover, we utilized the CTRP and GDSC databases to examine how drug sensitivity is related to mRNA expression of HAM-related genes. Results Based on our findings, bladder cancer could be divided into histone arginine methylation-low (HAM-low) and histone arginine methylation-high (HAM-high) subtypes with distinctive clinicopathological characteristics, tumor microenvironment and prognostic. There is a dismal prognosis associated with high histone arginine methylation subtypes and a high frequency of oncogene mutations in these subtypes. Conversely, histone arginine methylation-low subtypes are associated with a better clinical outcome and a lower frequency of oncogene mutations. There was a correlation between the HAM-high subtype and the immune-hot phenotype, while the HAM-low subtype was associated with the immune-cold phenotype. As well, we develop and validate a prognostic model associated with histone arginine methylation that has good predictive power. The results of drug sensitivity tests revealed that HAM-related genes are associated with resistance to most drugs. A positive correlation was found between XAV939 or Cetuximab and HAM-related gene expression, suggesting that these agents may be beneficial to patients who fall into the HAM-high subgroup of BC patients. Conclusion In summary, we have established a novel bladder classification based on histone arginine methylation subtypes. This classification has significant consequences for the estimation of prognosis and drug sensitivity, as well as the tumor microenvironment.

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PRMT5-activated c-Myc promote bladder cancer proliferation and invasion through up-regulating NF-κB pathway

Cited by 10 publications

References 28 publications

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality

Identification of molecular subtypes based on histone arginine methylation in bladder cancer

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