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

ABSTRACT: 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.

SUBMITTER: Sloan SL

PROVIDER: S-EPMC8121334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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

Project description:Targeting PRMT5 in canine lymphoma: we characterized expression patterns of PRMT5 in canine lymphomas and correlated these with histological subtypes using tissue microarrays. We characterized expression of PRMT5 in three canine lymphoma-derived cell lines and primary lymph node biopsies. We have demonstrated that inhibition of PRMT5 leads to growth suppression and induction of apoptosis in canine lymphoma cell lines and primary canine lymphoma cells in a time and dose-dependent manner, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric di-methylation. We performed ATAC-sequencing with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility after PRMT5 inhibition. We performed gene expression microarrays with pathway analysis to characterize whole transcriptome changes in canine lymphoma cell lines treated with PRMT5 inhibitors. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued used of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

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Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma.

Project description:Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.

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

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