PRMT5 silencing selectively affects MTAP-deleted mesothelioma: In vitro evidence of a novel promising approach.

Abstract

Malignant mesothelioma (MM) is an aggressive asbestos-related cancer of the serous membranes. Despite intensive treatment regimens, MM is still a fatal disease, mainly due to the intrinsic resistance to current therapies and the lack of predictive markers and new valuable molecular targets. Protein arginine methyltransferase 5 (PRMT5) inhibition has recently emerged as a potential therapy against methylthioadenosine phosphorylase (MTAP)-deficient cancers, in which the accumulation of the substrate 5'-methylthioadenosine (MTA) inhibits PRMT5 activity, thus sensitizing the cells to further PRMT5 inhibition. Considering that the MTAP gene is frequently codeleted with the adjacent cyclin-dependent kinase inhibitor 2A (CDKN2A) locus in MM, we assessed whether PRMT5 could represent a therapeutic target also for this cancer type. We evaluated PRMT5 expression, the MTAP status and MTA content in normal mesothelial and MM cell lines. We found that both administration of exogenous MTA and stable PRMT5 knock-down, by short hairpin RNAs (shRNAs), selectively reduced the growth of MTAP-deleted MM cells. We also observed that PRMT5 knock-down in MTAP-deficient MM cells reduced the expression of E2F1 target genes involved in cell cycle progression and of factors implicated in epithelial-to-mesenchymal transition. Therefore, PRMT5 targeting could represent a promising new therapeutic strategy against MTAP-deleted MMs.

• Authors: Marcella Barbarino, Daniele Cesari, Maria Bottaro, Luca Luzzi, Asadoor Namagerdi, Franca Maria Bertolino, Cristiana Bellan, Fabrizio Proietti, Pasquale Somma, Mariacarolina Micheli, Maria Margherita de Santi, Raffaella Guazzo, Luciano Mutti, Luigi Pirtoli, Piero Paladini, Paola Indovina, Antonio Giordano
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 10 Pg. 5565-5577 (05 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32301278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase

Topics

• Cell Line, Tumor
• Chromatography, Liquid
• Epithelial-Mesenchymal Transition (genetics)
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Silencing
• Humans
• Immunohistochemistry
• Mesothelioma (genetics, metabolism, pathology)
• Protein-Arginine N-Methyltransferases (genetics)
• Purine-Nucleoside Phosphorylase (genetics)
• Tandem Mass Spectrometry