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

Vollständiger Abstract

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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.