MST2 Methylation by PRMT5 Inhibits Hippo Signaling and Promotes Pancreatic Cancer Progression

As a classic tumor suppressor pathway, Hippo signaling axis is activated by various extra-pathway factors to regulate cell differentiation and organ development. However, recent studies have reported that the activation of Hippo signaling pathway may be more dependent on the autophosphorylation of its core kinase cassette. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) is involved in inducing the inactivation of Hippo signaling pathway in pancreatic cancer. Our study shows that the initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated at arginine-461 (R461) and arginine-467 (R467) in the SARAH domain by PRMT5, and the methylated MST2 suppresses its autophosphorylation and kinase activity by blocking the formation of homodimer, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also discover that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human-derived pancreatic cancer xenografts in immunodeficient mice, which provides a theoretical foundation for the clinical application of PRMT5 inhibitor in pancreatic cancer. Comparative gene expression profiling analysis of RNA-seq data for the pancreatic cancer cells after kncokdown of PRMT5.

作为经典的肿瘤抑制通路，Hippo信号轴（Hippo signaling axis）可被多种通路外因子激活，进而调控细胞分化与器官发育。然而，近期研究表明，Hippo信号通路的激活或许更依赖于其核心激酶组件的自身磷酸化。本研究证实，蛋白精氨酸甲基转移酶5（PRMT5）可参与诱导胰腺癌中Hippo信号通路的失活。研究发现，Hippo信号通路的起始丝氨酸/苏氨酸激酶3（STK3，又称MST2）可在SARAH结构域内的精氨酸461位（R461）与精氨酸467位（R467）位点发生PRMT5介导的对称二甲基化；经甲基化修饰的MST2会通过阻断同源二聚体的形成，抑制其自身磷酸化与激酶活性，最终使胰腺癌中的Hippo信号通路失活。此外，本研究还发现，特异性PRMT5抑制剂GSK3326595可重新激活失调的Hippo信号通路，并在免疫缺陷小鼠体内抑制人源胰腺癌异种移植瘤的生长，这为PRMT5抑制剂在胰腺癌中的临床应用提供了理论基础。本研究同时对PRMT5基因敲低后的胰腺癌细胞进行了RNA测序（RNA-seq）数据的比较基因表达谱分析。