PRMT5 Regulates Cell Pyroptosis By Silencing CASP1 in Multiple Myeloma

Tian Xia,Ming Liu,Quan Zhao,Rongfu Zhou,Bing Chen,Peipei Xu

doi:10.1182/blood-2021-147092

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. DisclosuresNo relevant conflicts of interest to declare.

Highlights

Multiple myeloma (MM) is a malignancy that originates from the extensive proliferation of pathological antibody-producing plasma cells in the bone marrow and accounts for ~10% of hematological cancers [1]
We explored the biological function of Protein arginine methyltransferase 5 (PRMT5) in MM cells and investigated the mechanism by which PRMT5 regulates MM cell pyroptosis by repressing CASP1
Further bioinformatics analysis combining the Myeloma Research Foundation (MMRF) CoMMpass (n = 859) and Genotype-Tissue Expression (GTEx) databases (n = 62) was conducted, which revealed that PRMT5 expression was higher in MM tissues than in noncancerous tissues (P = 0.00034, Fig. 1B)

Summary

INTRODUCTION

Multiple myeloma (MM) is a malignancy that originates from the extensive proliferation of pathological antibody-producing plasma cells in the bone marrow and accounts for ~10% of hematological cancers [1]. Protein arginine methyltransferase 5 (PRMT5) is the main type II methyltransferase that catalyzes the symmetric addition of dimethylarginine to histone proteins, nonhistone proteins, and cytoplasmic proteins and is involved in numerous cellular processes, including transcription, DNA repair, RNA processing, proliferation, and metabolism [9,10,11]. Several studies have demonstrated that PRMT5 is overexpressed in hematological malignancies, including leukemia, lymphoma, and MM [12]. In addition to our cohort, we extracted clinical and RNA sequencing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study to assess the clinical significance of PRMT5. We explored the biological function of PRMT5 in MM cells and investigated the mechanism by which PRMT5 regulates MM cell pyroptosis by repressing CASP1

RESULTS

DISCUSSION

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