ZFWang_lab_NODEX00000037

Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway.剪接失调（splicing dysregulation）广泛存在于癌症中，但此类改变的生物学后果大多尚未明确。本研究报道，调控细胞增殖与器官大小的关键通路——Hippo-YAP信号通路（Hippo-YAP signaling），受一种新型可变剪接（alternative splicing）开关的调控。研究显示，介导该信号通路的转录因子TEAD4，可在肿瘤抑制因子RBM4的介导下发生可变剪接，产生截短型异构体TEAD4-S；该异构体缺失N端DNA结合结构域（N-terminal DNA-binding domain），但保留YAP相互作用结构域（YAP-interaction domain）。TEAD4-S同时分布于细胞核与细胞质中，可作为YAP活性的显性负性异构体发挥作用。实验结果与此相符：癌细胞中TEAD4-S的表达水平显著降低，重新表达TEAD4-S可抑制癌细胞的增殖与迁移，并在异种移植小鼠模型（xenograft mouse model）中阻滞肿瘤生长。此外，人类癌症组织中TEAD4-S的表达同样下调，TEAD4-S水平升高的患者生存率更高。综上，本研究揭示了一种由RBM4介导的新型可变剪接开关，该开关可精准调控Hippo-YAP信号通路。