PRMT5 Enables Robust STAT3 Activation via Arginine Symmetric Dimethylation of SMAD7

Abstract Protein arginine methyltransferase 5 (PRMT5) is the type II arginine methyltransferase that catalyzes the mono‐ and symmetrical dimethylation of protein substrates at the arginine residues. Emerging evidence reveals that PRMT5 is involved in the regulation of tumor cell proliferation and cancer development. However, the exact role of PRMT5 in human lung cancer cell proliferation and the underlying molecular mechanism remain largely elusive. Here, it is shown that PRMT5 promotes lung cancer cell proliferation through the Smad7‐STAT3 axis. Depletion or inhibition of PRMT5 dramatically dampens STAT3 activation and thus suppresses the proliferation of human lung cancer cells. Furthermore, depletion of Smad7 blocks PRMT5‐mediated STAT3 activation. Mechanistically, PRMT5 binds to and methylates Smad7 on Arg‐57, enhances Smad7 binding to IL‐6 co‐receptor gp130, and consequently ensures robust STAT3 activation. The findings position PRMT5 as a critical regulator of STAT3 activation, and suggest it as a potential therapeutic target for the treatment of human lung cancer.