Hippo信号通路分子机制的化学生物学研究及其抗癌应用

Hippo信号通路是最近发现的一条通过调控细胞增殖、凋亡及干细胞自我更新控制多细胞生物器官大小的信号途径。研究表明Hippo通路的异常导致癌症发生。以往的研究通过传统微观生物学和模式动物方法阐明了该通路的主要成员和生理功能。然而该通路的一些关键分子机制尚未阐明， 其作为抗癌新靶标的可能性亟待研究。本项目拟采用化学生物学手段，在已完成的Hippo通路效应分子YAP/TAZ抑制剂筛选的基础上阐明抑制剂的直接靶蛋白及其在Hippo通路上的作用位点，从这一角度出发阐明Hippo通路调控和功能的新分子、新机制。通过对YAP抑制剂敏感的细胞分子标记研究我们进一步阐明Hippo通路与其它信号通路的相互作用。在此基础上研究YAP抑制剂在体内外的抑癌效果。本项目将从独特的角度发现Hippo通路的新机制，为Hippo通路研究提供便利的化学工具，为Hippo通路靶向性抗癌药物的开发提供先导化合物。

The recently established Hippo signaling pathway plays an evolutionarily conserved role in organ size control by inhibiting cell proliferation, promoting apoptosis, and regulating stem cell self-renewal. Evidence supports that deregulation of the Hippo pathway is involved in pathogenesis of multiple human cancers. In the past decade, core components and physiological roles of the Hippo pathway have been elucidated using traditional molecular biology, cell biology, and genetics approaches. However, key questions regarding molecular mechanisms of the Hippo pathway remain, such as the underlying mechanism of Hippo pathway regulation by mechanical stress and GPCR signaling. In addition, the possibility of Hippo pathway as a novel cancer therapy target awaits validation in vitro and in vivo. Here we propose a project using chemical biology approach to study molecular mechanisms of the Hippo pathway. We have accomplished a screen for YAP/TAZ inhibitors in our preliminary study. We would first determine the Hippo pathway components affected by the inhibitors and identify direct target proteins of these inhibitors. By analyzing how the targets of inhibitors function, we identify novel components and mechanisms of the Hippo pathway. Using YAP inhibitors we further decode molecular markers that predict sensitivity of cancer cells to YAP inhibition, which would not only direct application of anti-YAP cancer therapy but also suggest interaction of the Hippo pathway with other signaling events. Furthermore, we analyze the efficacy of YAP inhibition in inhibiting cancer cell survival in vitro and tumor growth in vivo. The project approaches the molecular mechanisms of the Hippo pathway from a unique angle and will possibly provide convenient chemical tools for research of the Hippo pathway and lead compounds for drug development.