CARM1 in human cancer: a multifunctional epigenetic node driving tumor plasticity and therapeutic vulnerability.
Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a signal-responsive epigenetic regulator that couples oncogenic and stress signals to chromatin, transcription, RNA processing, metabolism, and genome maintenance. Its effects arise from both asymmetric arginine methylation of histone and non-histone substrates and methyltransferase-independent scaffolding activities. This review critically synthesizes the structural basis, substrate networks, methylarginine readers, and cancer-contextual functions of CARM1. We propose that its apparently opposing oncogenic and tumor-suppressive activities are determined by lineage-specific substrates, regulatory post-translational modifications, cofactor and chromatin availability, and stage- or microenvironment-dependent stress signals. We further evaluate CARM1-directed therapy using an evidence-graded framework. Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene.