Laboratory of Molecular Analysis, Nippon Medical School, Tokyo, Japan.
Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.
Commun Biol. 2024 May 17;7(1):593. doi: 10.1038/s42003-024-06290-7.
STAT3 is constitutively activated in many cancer types, including lung cancer, and can induce cancer cell proliferation and cancer stem cell (CSC) maintenance. STAT3 is activated by tyrosine kinases, such as JAK and SRC, but the mechanism by which STAT3 maintains its activated state in cancer cells remains unclear. Here, we show that PRMT5 directly methylates STAT3 and enhances its activated tyrosine phosphorylation in non-small cell lung cancer (NSCLC) cells. PRMT5 expression is also induced by STAT3, suggesting the presence of a positive feedback loop in cancer cells. Furthermore, methylation of STAT3 at arginine 609 by PRMT5 is important for its transcriptional activity and support of tumour growth and CSC maintenance. Indeed, NSCLC cells expressing the STAT3 mutant which R609 was replaced to alanine (R609K) show significantly impaired tumour growth in nude mice. Overall, our study reveals a mechanism by which STAT3 remains activated in NSCLC and provides a new target for cancer therapeutic approaches.
STAT3 在许多癌症类型中持续激活，包括肺癌，并能诱导癌细胞增殖和癌症干细胞（CSC）维持。STAT3 被酪氨酸激酶激活，如 JAK 和 SRC，但 STAT3 在癌细胞中保持其激活状态的机制尚不清楚。在这里，我们表明 PRMT5 直接甲基化 STAT3 并增强非小细胞肺癌（NSCLC）细胞中 STAT3 的激活酪氨酸磷酸化。PRMT5 的表达也被 STAT3 诱导，表明癌细胞中存在正反馈回路。此外，PRMT5 对 STAT3 精氨酸 609 的甲基化对于其转录活性以及对肿瘤生长和 CSC 维持的支持至关重要。事实上，表达 STAT3 突变体（R609 被替换为丙氨酸的 R609K）的 NSCLC 细胞在裸鼠中显示出明显受损的肿瘤生长。总的来说，我们的研究揭示了 STAT3 在 NSCLC 中持续激活的机制，并为癌症治疗方法提供了一个新的靶点。
