PRMT5 Enables Robust STAT3 Activation via Arginine Symmetric Dimethylation of SMAD7

• Published in: Advanced science Vol. 8; no. 10; pp. 2003047 - n/a
• Main Authors: Cai, Congcong, Gu, Shuchen, Yu, Yi, Zhu, Yezhang, Zhang, HanChenxi, Yuan, Bo, Shen, Li, Yang, Bing, Feng, Xin‐Hua
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.05.2021; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Arginine - metabolism; Cell cycle; Cell Line, Tumor; Cell Proliferation; Humans; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Methylation; migration; Phosphorylation; PRMT5; Prognosis; proliferation; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Smad7; Smad7 Protein - chemistry; Smad7 Protein - metabolism; STAT3; STAT3 Transcription Factor - metabolism; Stem cells; Tumors; migration; PRMT5; proliferation; methylation; Smad7; STAT3
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202003047

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. The role of protein arginine methyltransferase 5 (PRMT5) in Janus kinase (JAK)‐signal transducer and activator of transcription 3 (STAT3) signaling pathway and lung cancer cell proliferation is unveiled. PRMT5 symmetrically dimethylates Smad7 on Arginine‐57, promotes Smad7 binding to interleukin‐6 (IL‐6) co‐receptor glycoprotein 130 (gp130), and consequently ensures robust STAT3 activation in a transforming growth factor‐β (TGF‐β) independent manner. This finding positions PRMT5 as a promising therapeutic target for lung cancer treatment.