PRMT5 maintains tumor stem cells to promote pediatric high-grade glioma tumorigenesis

Abstract

AbstractBackgroundPediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a screen for epigenetic regulators, we identifiedPRMT5as essential for PHGG growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth.Methods. We conductedin vitroassays, including limiting dilution studies of self-renewal, to determine the phenotypic effects ofPRMT5KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting fromPRMT5KD or administration of a PRMT5 inhibitor ± radiation therapy (RT).ResultsIn vitro,PRMT5KD slowed cell cycle progression, tumor growth and self-renewal.PRMT5KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth.In vivo,PRMT5KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival.ConclusionPRMT5KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failedin vivodue to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.ImplicationsOur findings show the importance ofPRMT5to maintain and promote the growth of stemlike cells that initiate and drive tumorigenesis in pediatric high grade glioma.