STMC-07. PRMT5-PTEN MOLECULAR PATHWAY REGULATES SENESCENCE AND SELF-RENEWAL OF GLIOBLASTOMA NEUROSPHERES

Abstract

Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumor cell population including mature non-stem like cell and immature stem-like cells within the tumor. 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 tumor 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 Rb protein, leading to senescence. Comparison of impact of PRMT5 on cellular signaling by Human Phospho-Kinase Array and ChIP-PCR revealed that unlike GBMDC, PRMT5 controls both AKT and ERK activity by direct repression of PTEN in GBMNS. In vivo transient depletion of PRMT5 decreased intracranial tumor size and growth rate in mice implanted with both primary tumor derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and vital to support both mature and immature GBM tumor cell populations.