Arginine methylation as a regulatory ratchet in cancer: From substrate selection to malignant-state stabilization

Arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is a widespread post-translational modification yet its regulatory logic in cancer remains incompletely framed. Unlike rapidly reversible modifications, arginine methylation operates through a persistence-prone, forward-biased logic shaped by the lack of a broadly acting demethylase system, multisite substrates, and ongoing methylation flux. Here, we propose a regulatory ratchet framework in which PRMT-dependent methylation can reinforce cellular states through cumulative and network-level effects rather than acting as a binary switch. We integrate PRMT subtype specificity and noncatalytic functions with a four-layer model of substrate selection spanning sequence, structural, localization, and environmental context. Persistence may arise at both mark and flux levels, while scaffold-like PRMT functions may sustain regulatory complexes independently of catalysis. In cancer, PRMT-compatible substrates are distributed across RNA processing, chromatin and transcriptional regulation, signaling, and metabolism, with methylation output shaped by dynamic inter-PRMT relationships. Together, these network-level interactions may reinforce cancer cell states while creating therapeutic vulnerabilities within a constrained methylation system, shifting attention from individual PRMT abundance toward the network architecture that sustains malignant programs.