Yap蛋白去泛素化的分子机制研究及其在结肠癌中的病理意义

The Hippo Pathway is an evolutionary conserved signaling pathway critical in regulating tissue homeostasis and organ size of multicellular organisms, and its dysregulation often results in tumorigenesis. The oncoprotein Yap is the key downstream effector the Hippo pathway, and its protein levels are frequently elevated in human cancers. The protein level of Yap is mainly controlled by ubiquitination and proteasomal degradation, and the E3 ubiquitin ligase responsible for Yap poly-ubiquitination has been well characterized, however a dedicated deubiquitination enzyme for Yap remains elusive. Our preliminary results indicate that USP is a potential deubiquitination enzyme for Yap, as USP can interact with Yap, induce Yap deubiquitination, and increase Yap protein stability. We have also discovered that the protein levels of both Yap and USP are upregulated in colorectal cancer specimens, indicating that USP might be responsible for high Yap expression in human cancers. Based on our preliminary results, we will characterize the molecular mechanisms underlying Yap deubiquitination by USP, and we will also use both transgenic mouse model and human cancer specimens to study the physiological and pathological function of USP-Yap regulation. In addition, we will test available Yap inhibitor on tumorigenic activity of colorectal cancer cells dependent on high USP activity. These studies will not only shed lights on the regulatory mechanisms of the Hippo pathway, but also provide novel molecular targeted therapies for colorectal cancer and some other types of cancer.

Hippo通路是一条调控机体器官大小的信号转导通路，该通路也同多种癌症的发生发展密切相关。Yap是Hippo通路的关键下游分子，它的蛋白水平在多种癌症样本中显著升高。Yap蛋白的稳定性主要受到泛素化的调节，现在已经发现导致Yap泛素化的E3泛素连接酶，但是Yap的去泛素化酶还未见报道。由于Yap蛋白稳定性可能同其在癌症中的高表达相关，因此迫切需要加强Yap泛素化(特别是去泛素化)的研究。我们前期实验表明USP可能就是Yap去泛素化酶。在结肠癌样本中，USP和Yap都在癌变组织中高表达，并且呈正相关性。因此，USP可能通过增强Yap稳定性导致结肠癌的发生。基于前期工作，本课题将进一步研究USP调控Yap泛素化的分子机制，并验证Yap小分子抑制剂对USP高表达结肠癌的抗癌效果。这一系列的研究不仅可以拓展对Hippo通路调控机制的理解，还可能为结肠癌等肿瘤的治疗提供新的治疗思路。

Hippo通路是一条调控机体器官大小的信号转导通路，该通路也同多种癌症的发生发展密切相关。Yap是Hippo通路的关键下游分子，它的蛋白水平在多种癌症样本中显著升高。Yap蛋白的稳定性主要受到泛素化的调节，现在已经发现导致Yap泛素化的E3泛素连接酶，但是Yap的去泛素化酶还未见报道。由于Yap蛋白稳定性可能同其在癌症中的高表达相关，因此迫切需要加强Yap泛素化(特别是去泛素化)的研究。本项目研究发现USP47是Yap去泛素化酶，能够调节Yap在大肠癌细胞中的稳定性及转录活性。在大肠癌样本中，USP47和Yap都在癌变组织中高表达，并且呈正相关性。USP47通过增强Yap稳定性导致大肠癌的发生。另外USP47小分子抑制剂对Yap高表达大肠癌细胞生长有较好的抑制效果。这一系列的研究不仅可以拓展对Hippo通路调控机制的理解，还可能为结大肠癌等肿瘤的治疗提供新的治疗思路。