PRMT5 inhibition induces a histone methylation switch that drives chromatin plasticity, drug resistance, and metastatic progression

PRMT5 is the major type II protein arginine methyltransferase, regulating fundamental processes including transcription, splicing, and translation. Its expression is restricted to stem and progenitor cells but reactivated in many tumors. Numerous PRMT5 inhibitors (PRMT5i) have been developed, and several are currently in clinical trials. Their efficacy is largely attributed to disruption of PRMT5's role in splicing. Here we show that PRMT5i produce dichotomous effects in lung adenocarcinoma (LUAD): they induce lethal splicing defects but also trigger epigenetic changes that actively enable acquisition of drug resistance. Of concern, the resulting stably resistant populations have undergone accelerated dedifferentiation, gaining molecular and phenotypic hallmarks of metastatic disease. Moreover, even brief PRMT5i treatment of drug-naive tumors is sufficient to drive disease progression in vivo. This epigenetic rewiring reflects a previously unappreciated dominance of PRMT5 over PRMT1, arising from differential subcellular localization. Our data indicate that cytoplasmic PRMT5 likely dimethylates histones symmetrically before nuclear import. PRMT5i block this, allowing unmodified histones to reach nuclear PRMT1 and undergo asymmetric dimethylation instead. This symmetric-to-asymmetric switch flips histones from repressive to activating states, yielding rapid chromatin opening and derepression of lineage programs, a subset of which are selected for and retained in resistant cells. Accordingly, inhibition of asymmetric dimethylation suppresses PRMT5i-induced chromatin derepression and synergizes strongly with PRMT5 inhibition. Finally, endogenous PRMT5 suppression in MTAP-deficient human cells partially engages this switch, and CDKN2A/MTAP-deficient tumors are correspondingly more dedifferentiated. Thus, PRMT5i create a splicing vulnerability while simultaneously licensing epigenetic escape toward a more dedifferentiated and aggressive cell state.