Chai Jiwei, Xu Shijie, Guo Fengbo
The Second Department of Trauma Surgery, Linyi People's Hospital, Linyi 276000, PR China.
Chinese Medicine Department of Orthopedics, Linyi People's Hospital, Linyi 276000, PR China.
Biochem Biophys Res Commun. 2017 Jun 24;488(2):297-302. doi: 10.1016/j.bbrc.2017.05.032. Epub 2017 May 5.
Hippo signaling pathway is an evolutionarily conserved developmental network that governs the downstream transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs that responsible for cell proliferation, apoptosis, and stem cell self renewal. Emerging evidence has shown the tumor suppressor properties of Hippo signaling. However, limited knowledge is available concerning the downstream transcription factors of Hippo pathway in osteosarcoma (OS). In this study, we demonstrated that TEAD1 was the major transcription factor of Hippo signaling pathway in OS. Genetic silencing of TEAD1 suppressed multiple malignant phenotypes of OS cells including cell proliferation, apoptosis resistance, and invasive potential. Mechanistically, we showed that TEAD1 largely exerted its transcriptional control of its functional targets, PTGS2 and CYR61. Collectively, this work identifies the YAP1/TEAD1 complex as the representative dysregulated profile of Hippo signaling in OS and provides proof-of-principle that targeting TEAD1 may be a therapeutic strategy of osteosarcoma.
河马信号通路是一个进化上保守的发育网络，它调控下游转录共激活因子YAP和TAZ，这两个因子与TEADs结合并激活其输出，而TEADs负责细胞增殖、凋亡和干细胞自我更新。新出现的证据表明了河马信号通路具有肿瘤抑制特性。然而，关于骨肉瘤（OS）中河马信号通路的下游转录因子，人们了解有限。在本研究中，我们证明TEAD1是骨肉瘤中河马信号通路的主要转录因子。TEAD1的基因沉默抑制了骨肉瘤细胞的多种恶性表型，包括细胞增殖、抗凋亡能力和侵袭潜能。从机制上来说，我们表明TEAD1主要通过对其功能靶点PTGS2和CYR61进行转录控制来发挥作用。总的来说，这项工作确定了YAP1/TEAD1复合物是骨肉瘤中河马信号通路失调的代表性特征，并提供了原理证明，即靶向TEAD1可能是骨肉瘤的一种治疗策略。
