PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma

Xia, Tian; Liu, Ming; Zhao, Quan; Ouyang, Jian; Xu, Peipei; Chen, Bing

doi:10.1038/s41419-021-04125-5

Cited by 24 publications

(15 citation statements)

References 47 publications

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“…In addition, its release of massive amounts of inflammatory cytokines induced a potent immune response, which ultimately reshapes TME ( 11 ). Till date, few studies demonstrated a link between pyroptosis and MM ( 12 , 13 ). Moreover, the significance of pyroptosis-related genes (PRGs) in MM prognosis is undetermined.…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma

Wang

Shao

et al. 2022

Front. Oncol.

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PurposePyroptosis is an inflammation-based programmed cell death that holds great potential as a novel cancer therapeutic target in patients with multiple myeloma (MM). However, thus far, the function of pyroptosis-related genes (PRGs) in MM and their prognostic relevance remains undetermined.MethodsThe model was established by the LASSO analysis, based on the Gene Expression Omnibus (GEO) dabatase, and its efficacy was verified using two external datasets. The model’s predictive ability was assessed by the Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves. Finally, a nomogram was established for clinical application. We also confirmed the validity of our model using specimens and in vitro experiments.ResultsWe established an 11-PRG signature profile, and verified its efficacy using two validation cohorts (VCs). In both cohorts, patients were separated into two subpopulations, according to their median risk scores (RS). Our analysis revealed that high-risk (HR) patients experienced considerably lower overall survival (OS), compared to the low-risk (LR) patients. Using functional enrichment and immune infiltration analyses, we demonstrated that the immunologic status was strongly related to RS. Furthermore, using a pyroptosis inhibitor Q-VD-OPh, we revealed that MM cell proliferation and progression was drastically suppressed and the doxorubicin (DOX)-induced apoptosis was reversed.ConclusionBased on our analysis, pyroptosis not only serves as a measure of MM treatment efficiency and patient prognosis, but is also a possible target for anti-MM therapy.

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Section: Introductionmentioning

confidence: 99%

Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma

Wang

Shao

et al. 2022

Front. Oncol.

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“…There is evidence that pyrotosis plays a role in the occurrence and development of MM. Xia et al 22 found that PRMT5 regulates pyroptosis by silencing CASP1 in MM. Zmorzyński et al 23 found that the NOD2/CARD15 variant (3020insc) and PS6 polymorphism affect the occurrence and prognosis of MM.…”

Section: Introductionmentioning

confidence: 99%

Construction of a Prognosis Model of the Pyroptosis-Related Gene in Multiple Myeloma and Screening of Core Genes

Liang

Bian

et al. 2022

ACS Omega

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Pyroptosis is an important factor affecting the proliferation, invasion, and metastasis of tumor cells. However, in multiple myeloma (MM), there are few studies on whether the occurrence of pyroptosis is related to the occurrence and prognosis of the disease. Based on the Gene Expression Omnibus and Cancer Genome Atlas database search dataset, this study identified pyroptosis-related genes with a specific prognosis, constructed and verified the prediction model by stepwise Cox regression analysis and time receiver operating characteristic curve analysis, and predicted specific functions by single-sample gene set enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes. Dataset analysis identified key genes, which were used to construct a risk scoring system for the prognosis of MM. The entire test set and external verification set verified the results. The expression levels of related genes in the clinical samples were detected using fluorescence quantitative PCR. A prognostic gene model based on six pyroptosis-related genes (CYCS, NLRP9, AIM2, NOD2, CHMP3, and GSDME) was constructed. The model has an excellent prognostic ability and can be popularized in the external validation set. The predictive prognostic nomogram integrating clinical information can effectively evaluate the risk score of each patient and predict their survival. After sample validation, our study found three potential key pyroptosis-related genes in multiple myeloma. GSDME, NOD2, and CHMP3 were significantly different between MM and healthy subjects, suggesting that they are pyroptosis-related protective genes. This study shows that the key pyroptosis-related gene in the model can be used as a marker for predicting the prognosis of myeloma, which may provide a basis for clinical individualized stratification therapy.

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“…In MM cell lines, PRMT5 controls pyroptosis through the silencing of caspase 1 ( CASP1 ). The knockdown of PRMT5 induces CASP1 and cleaved CASP1 expression, and pyroptosis could be rescued in this model by knocking down CASP1 [ 70 ].…”

Section: Involvement Of Prmts In Hematopoiesis and Hematological Mali...mentioning

confidence: 99%

“…In MM cell lines, treatment with a PRMT5 inhibitor decreases the levels of H4R3me2s at the CASP1 promoter, thus, enhancing the pyroptosis of myeloma cells [ 70 ]. A decrease in cell proliferation and an increase in apoptosis are also demonstrated in MM with a PRMT5 inhibitor.…”

Section: Pharmacological Inhibition Of Prmts In Hematological Maligna...mentioning

confidence: 99%

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

Sauter

Simonet

Guidez

et al. 2022

Cancers

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Arginine methylation is a common post-translational modification affecting protein activity and the transcription of target genes when methylation occurs on histone tails. There are nine protein arginine methyltransferases (PRMTs) in mammals, divided into subgroups depending on the methylation they form on a molecule of arginine. During the formation and maturation of the different types of blood cells, PRMTs play a central role by controlling cell differentiation at the transcriptional level. PRMT enzymatic activity is necessary for many cellular processes in hematological malignancies, such as the activation of cell cycle and proliferation, inhibition of apoptosis, DNA repair processes, RNA splicing, and transcription by methylating histone tails’ arginine. Chemical tools have been developed to inhibit the activity of PRMTs and have been tested in several models of hematological malignancies, including primary samples from patients, xenografts into immunodeficient mice, mouse models, and human cell lines. They show a significant effect by reducing cell viability and increasing the overall survival of mice. PRMT5 inhibitors have a strong therapeutic potential, as phase I clinical trials in hematological malignancies that use these molecules show promising results, thus, underlining PRMT inhibitors as useful therapeutic tools for cancer treatment in the future.

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PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma

Cited by 24 publications

References 47 publications

Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma

Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma

Construction of a Prognosis Model of the Pyroptosis-Related Gene in Multiple Myeloma and Screening of Core Genes

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

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