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PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma.

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5), a histone methyltransferase responsible for the symmetric dimethylation of histone H4 on Arg 3 (H4R3me2s), is an enzyme that participates in tumor cell progression in a variety of hematological malignancies. However, the biological functions of PRMT5 in multiple myeloma (MM) and the underlying molecular mechanisms remain unclear. In this study, we conducted a bioinformatics analysis and found that PRMT5 expression was significantly upregulated in MM. In vitro and in vivo phenotypic experiments revealed that knockdown of PRMT5 expression enhanced cell pyroptosis in MM. Moreover, we found that CASP1 expression was negatively correlated with PRMT5 expression, and repressing PRMT5 expression rescued both the phenotype and expression markers (N-GSDMD, IL-1b, and IL-18). Inhibition of PRMT5 activity increased CASP1 expression and promoted MM cell pyroptosis. Finally, high expression of PRMT5 or low expression of CASP1 was correlated with poor overall survival in MM. Collectively, our results provide a mechanism by which PRMT5 regulates cell pyroptosis by silencing CASP1 in MM.

SUBMITTER: Xia T

PROVIDER: S-EPMC8445991 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma.

Xia Tian T Liu Ming M Zhao Quan Q Ouyang Jian J Xu Peipei P Chen Bing B

Cell death & disease 20210916 10

Protein arginine methyltransferase 5 (PRMT5), a histone methyltransferase responsible for the symmetric dimethylation of histone H4 on Arg 3 (H4R3me2s), is an enzyme that participates in tumor cell progression in a variety of hematological malignancies. However, the biological functions of PRMT5 in multiple myeloma (MM) and the underlying molecular mechanisms remain unclear. In this study, we conducted a bioinformatics analysis and found that PRMT5 expression was significantly upregulated in MM. ...[more]

PMID: 34531375

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Project description:BackgroundSertoli cell-only syndrome (SCOS) is the most serious pathological type of non-obstructive azoospermia. Recently, several genes related to SCOS have been identified, including FANCM, TEX14, NR5A1, NANOS2, PLK4, WNK3, and FANCA, but they cannot fully explain the pathogenesis of SCOS. This study attempted to explain spermatogenesis dysfunction in SCOS through testicular tissue RNA sequencing and to provide new targets for SCOS diagnosis and therapy.MethodsWe analyzed differentially expressed genes (DEGs) based on RNA sequencing of nine patients with SCOS and three patients with obstructive azoospermia and normal spermatogenesis. We further explored the identified genes using ELISA and immunohistochemistry.ResultsIn total, 9406 DEGs were expressed (Log2|FC|≥ 1; adjusted P value < 0.05) in SCOS samples, and 21 hub genes were identified. Three upregulated core genes were found, including CASP4, CASP1, and PLA2G4A. Thus, we hypothesized that testis cell pyroptosis mediated by CASP1 and CASP4 might be involved in SCOS occurrence and development. ELISA verified that CASP1 and CASP4 activities in the testes of patients with SCOS were significantly higher than those in patients with normal spermatogenesis. Immunohistochemical results showed that CASP1 and CASP4 in the normal spermatogenesis group were mainly expressed in the nuclei of spermatogenic, Sertoli, and interstitial cells. CASP1 and CASP4 in the SCOS group were mainly expressed in the nuclei of Sertoli and interstitial cells because of the loss of spermatogonia and spermatocytes. CASP1 and CASP4 expression levels in the testes of patients with SCOS were significantly higher than those in patients with normal spermatogenisis. Furthermore, the pyroptosis-related proteins GSDMD and GSDME in the testes of patients with SCOS were also significantly higher than those in control patients. ELISA also showed that inflammatory factors (IL-1 β, IL-18, LDH, and ROS) were significantly increased in the SCOS group.ConclusionsFor the first time, we found that cell pyroptosis-related genes and key markers were significantly increased in the testes of patients with SCOS. We also observed many inflammatory and oxidative stress reactions in SCOS. Thus, we propose that testis cell pyroptosis mediated by CASP1 and CASP4 could participate in SCOS occurrence and development.

Project description:BackgroundMultiple myeloma (MM) is an incurable and relapse-prone disease with apparently prognostic heterogeneity. At present, the risk stratification of myeloma is still incomplete. Pyroptosis, a type of programmed cell death, has been shown to regulate tumor growth and may have potential prognostic value. However, the role of pyroptosis-related genes (PRGs) in MM remains undetermined. The aims of this study were to identify potential prognostic biomarkers and to construct a predictive model related to PRGs.MethodsSequencing and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Non-negative matrix factorization (NMF) was performed to identify molecular subtype screening. LASSO regression was used to screen for prognostic markers, and then a risk score model was constructed. The Maxstat package was utilized to calculate the optimal cutoff value, according to which patients were divided into a high-risk group and a low-risk group, and the survival curves were plotted using the Kaplan-Meier (K-M) method. Nomograms and calibration curves were established using the rms package.ResultsA total of 33 PRGs were extracted from the TCGA database underlying which 4 MM molecular subtypes were defined. Patients in cluster 1 had poorer survival than those in cluster 2 (p = 0.035). A total of 9 PRGs were screened out as prognostic markers, and the predictive ability of the 9-gene risk score for 3-year survival was best (AUC = 0.658). Patients in the high-risk group had worse survival than those in the low-risk group (p < 0.001), which was consistent with the results verified by the GSE2658 dataset. The nomogram constructed by gender, age, International Staging System (ISS) stage, and risk score had the best prognostic predictive performance with a c-index of 0.721.ConclusionOur model could enhance the predictive ability of ISS staging and give a reference for clinical decision-making. The new, prognostic, and pyroptosis-related markers screened out by us may facilitate the development of novel risk stratification for MM.Clinical trial registrationNot applicable.

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PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma.

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PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma.

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