PRMT5-PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells.
Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumour growth in mice. Here, we report the critical role of PRMT5 in GBM differentiated cells (GBMDC) grown in serum and GBM neurospheres (GBMNS) grown as neurospheres in vitro. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS. In vivo transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations.
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Banasavadi-Siddegowda
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Russell
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Frair
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Karkhanis
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Relation
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Yoo
Department of Biomedical Informatics, Center for Biostatistics, Columbus, OH, USA.
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Zhang
Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
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Sif
Laboratory for Neural Stem Cells and Functional Neurogenetics, Division of Neuroimmunology and Multiple Sclerosis, Departments of Neurology and Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Imitola
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Baiocchi
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Kaur
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D000066673:Cell Self Renewal; D016922:Cellular Senescence; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism
C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human