EPCO-40. CARM1 IS A NOVEL TUMOR SUPPRESSOR IN GLIOBLASTOMA THAT REGULATES QKI THROUGH ARGININE METHYLATION

Abstract

Abstract Glioblastoma (GBM) is the most common form of primary brain tumor, characterized by dismal patient prognosis. Current pharmacological interventions have not significantly improved patient outcomes due to intratumor heterogeneity and the persistence of glioma stem cells (GSCs) that drive invasion and resistance. Thus, treatment strategies based on a deeper molecular understanding of gliomagenesis are urgently needed. Quaking (Qki, encoded by the gene Qk) is frequently altered in GBM; Qk mutations or deletions occur in 35% percent of cases, and the Qki protein is absent in 50-60% of cases. Our lab found that deletion of Qk in Trp53-/-; Pten-/- pre-malignant neural stem cells (NSCs) enables them to expand outside their niche and develop into malignant GBM. Mechanistically, we determined that Qki functions as a transcriptional coactivator of lipid metabolism genes in the central nervous system, where loss of Qki dysregulates the lipidome and alters cellular membrane integrity. While several downstream processes governed by Qki have been delineated, upstream regulators of Qki remain unknown. Recurrent cancer mutations to specific Qki arginine residues implicate the dysregulation of arginine methylation, and previous studies indicate that proteins in the same family as Qki can be methylated by protein arginine methyltransferases (PRMTs). Utilizing in vitro methylation assays, we demonstrate that Qki is selectively methylated by the PRMT coactivator-associated methyltransferase 1 (CARM1) in the Quaking regulatory domain (QRD), where cancer mutations were reported. Within the QRD, we identified arginine 242 (R242) and arginine 256 (R256) as specific CARM1-mediated methylation sites on Qki. Mutations to these sites compromise Qki transcriptional activity, as Qki methylation mutant-expressing GSCs exhibited downregulation of Qki target genes compared to those expressing wildtype Qki. Taken together, we provide evidence that CARM1 functions as a tumor suppressor in GBM through a novel mechanism of Qki dysregulation.