Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma

• Published in: PloS one Vol. 16; no. 5; p. e0250839
• Main Authors: Sloan, Shelby L, Renaldo, Kyle A, Long, Mackenzie, Chung, Ji-Hyun, Courtney, Lindsay E, Shilo, Konstantin, Youssef, Youssef, Schlotter, Sarah, Brown, Fiona, Klamer, Brett G, Zhang, Xiaoli, Yilmaz, Ayse S, Ozer, Hatice G, Valli, Victor E, Vaddi, Kris, Scherle, Peggy, Alinari, Lapo, Kisseberth, William C, Baiocchi, Robert A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.05.2021; Public Library of Science (PLoS)
• Subjects: Apoptosis; Arginine; Bioinformatics; Biology and Life Sciences; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell differentiation; Chemotherapy; Colorectal cancer; Cytotoxicity; Deoxyribonucleic acid; Diagnosis; Division; DNA; DNA damage; Dogs; Editing; Electronic mail; Epidermal growth factor receptors; Funding; Gene expression; Gene regulation; Health aspects; Hematology; Histones; Hodgkin's disease; Informatics; Information processing; Internal medicine; Leukemia; Lymphoma; Medicine; Medicine and Health Sciences; Methylation; Methyltransferases; NF-κB protein; Non-Hodgkin's lymphoma; Non-Hodgkin's lymphomas; p53 Protein; Protein arginine methyltransferase; Proteins; Rad9 protein; Research and Analysis Methods; Reviews; RNA processing; Signaling; Therapeutic targets; Transcription; Tumorigenesis; Veterinary colleges; Veterinary medicine; Visualization; United States; Delaware; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0250839

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.