Depletion of CARM1 slows in vivo tumorigenicity and rewires developmental programming in glioma stem-like cells.
Glioma stem-like cells (GSCs) exploit developmental signaling programs that contribute to glioblastoma heterogeneity and therapy resistance. Here, we define a role for the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1) in regulating GSC lineage state and survival signaling. CARM1 depletion slows GSC growth, increases apoptosis, alters histone post-translational modifications, and shifts transcriptomic and proteomic profiles toward a radial glial-like state. Loss of CARM1 increases NGFR/NTRK signaling and sensitizes GSCs to NTRK and AKT inhibition. Mechanistically, NFIA is a CARM1 substrate, and mutation of NFIA arginine 389 increases NGFR expression, supporting a role for CARM1-dependent NFIA methylation in NGFR repression. In orthotopic xenografts, CARM1 depletion reduces tumor burden and prolongs survival. These findings identify CARM1 as a regulator of GSC developmental programs and NGFR/NTRK-dependent survival.