The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China.
The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China.
Adv Sci (Weinh). 2021 Feb 24;8(10):2003047. doi: 10.1002/advs.202003047. eCollection 2021 May.
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.
蛋白质精氨酸甲基转移酶 5（PRMT5）是一种 II 型精氨酸甲基转移酶，可催化精氨酸残基上的蛋白质底物的单甲基化和对称二甲基化。新出现的证据表明，PRMT5 参与了肿瘤细胞增殖和癌症发展的调控。然而，PRMT5 在人肺癌细胞增殖中的确切作用及其潜在的分子机制在很大程度上仍不清楚。本研究表明，PRMT5 通过 Smad7-STAT3 轴促进肺癌细胞增殖。PRMT5 的耗竭或抑制显著抑制了 STAT3 的激活，从而抑制了人肺癌细胞的增殖。此外，Smad7 的耗竭阻断了 PRMT5 介导的 STAT3 激活。在机制上，PRMT5 结合并在 Arg-57 上甲基化 Smad7，增强了 Smad7 与白细胞介素 6 共受体 gp130 的结合，从而确保了强大的 STAT3 激活。这些发现将 PRMT5 定位为 STAT3 激活的关键调节因子，并表明其可能成为治疗人类肺癌的潜在治疗靶点。
