Hippo (hippopotamus). If the Hippo kinase have mutated, the fruit fly will have a huge head and a wrinkled neck that looks like a hippo.

Picture source: https://www.snopes.com

Hippo signal transduction pathway plays important roles in early development, organ size maintenance, tissue regeneration and tumorigenesis ^[1]. YAP co-transcriptional factor is a key effector molecule of the Hippo pathway, and its activity is mainly inhibited by the up-stream kinase LATS1/2. After modified by phosphorylation (S127 allele), YAP mainly localizes in the cytoplasm, without functioning to regulate gene transcription. In contrast, non-phosphorylated YAP is capable of translocating the nucleus and regulating a series of pro-proliferative, anti-apoptotic and cell-stemness related genes. At the same time, YAP is also an oncogenic protein with a high expression or nuclear localization in various tumors (such as colorectal cancer, liver cancer, etc.).

Although the activation of YAP in tumors is commonly existed, but the frequency of gene mutations in the Hippo pathway in tumors is not high, so the molecular mechanism leading to YAP activation remains to be revealed. Apart from phosphorylation modifications, can other post-translational modifications also modulate the activity of YAP, especially the subcellular localization of the YAP protein? Related research nowadays is a hot topic in the Hippo field, in which ubiquitination, methylation, and glycosylation have been found to modify YAP and regulate the activity of the latter ^[2-4]. The YAP ubiquitination modification was firstly reported by Guan Kunliang's research group of UCSD in 2010 (first author is Zhao Bin, who is now the PI of Zhejiang University Research Institute) ^[2], and glycosylation modification was reported by the Pei Huadong’s Research Group last year ^[4].

Prof. Wang Ping from Tongji University has studied the regulatory molecular mechanism of tumor microenvironment for post-translational modification of key signaling pathway proteins for a long time, and proposed new insights into the regulatory mechanisms of TOR and NFkB pathways. On June 29th, the latest issue of Cancer Cell published an online research paper from Prof. Wang Ping’s team, which entitled SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis, and clarified a new mechanism of Hippo pathway regulation and its role in tumorigenesis and development from the perspective of proteins’ post-translational modification.

In this work, it was found that the methyltransferase SET1A interacts with YAP and leads to the mono-methylation of 342 lysine (K342), which is closed to the nuclear NES of YAP, and the related modification can effectively block YAP. The interaction of nuclear factor CRM1 leads to the accumulation of YAP in the nucleus and enhances the expression of YAP-targeted genes. Functional studies further showed that K327M (equivalent to human YAPK342) knock-in mice with higher susceptibility to tumors, which is more likely to induce colorectal cancer in this mouse. At the same time, in clinical samples of colorectal cancer and lung cancer, SET1A is highly positive correlated with YAP K342 site methylation and can effectively predict the prognosis of patients. This work links the Hippo pathway to important epigenetic modification enzymes, not only revealing a novel mechanism of YAP regulation, but also providing a perfect explanation for how YAP is highly activated in tumors. Therefore, the work is not only very scientific, but also has a strong clinical significance.

Scientifically, this work reveals a new mechanism for the regulation of the Hippo pathway. We know that in addition to signal generation and transmission to effector molecules, the endurance of effects is also an important aspect. Many signal effects are time-sensitive (or chronergy), including YAP. For example, LPA and other signals activate YAP for only 1-4 hours. This finding suggests that the regulation of YAP by LATS1/2 kinase is the opening and closing of signal transduction, while SET1A can make the effect of YAP more persistent. In most cells, YAP is localized outside the nucleus in a phosphorylated state due to the presence of the upstream kinase LATS1/2. In this scenario, SET1A is not able to regulate YAP. When LATS1/2 kinase is turned off, YAP is dephosphorylated and translocated to the nucleus, SET1A can modify YAP by methylation, increase the retention time of YAP in the nucleus, and promote the transcriptional function of YAP.

In clinical transformation, this work reveals the mechanism of YAP activation in tumors, and methylation modification of YAP has also become a potential drug target. Meanwhile, in the prognosis of tumor patients, YAP K342me is better than YAP itself. High SET1A and high YAP K342me can identify the worst prognosis of patients. The relevant information may become an important basis for clinical judgment.

Prof.Wang Ping's new work is only the beginning of a series of findings. Further analysis of YAP K342M knock-in mice and SET1A mouse model will enable us to understand the regulation mechanism of Hippo pathway more deeply, and also for tumors. Precision treatment offers more ideas.

It is reported that the corresponding author of this paper is Prof. Wang Ping, Associate Dean of TUSM. Fang Lan, from Shanghai Tenth People's Hospital affiliated to Tongji University, Teng Hongqi from Tongji University, Wang Yilin from Shanghai Cancer Hospital affiliated to Fudan University and Liao Guanghong from Shanghai Key Laboratory of Regulatory Biology at East China Normal University are the co-first authors of this article.

Reference:

1.Yu, F. X., Zhao, B., & Guan, K. L. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 163(4), 811-828.

2.Zhao, B., Li, L., Tumaneng, K., Wang, C. Y., & Guan, K. L. (2010). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP. Genes & development, 24(1), 72-85.

3.Oudhoff, M. J., Freeman, S. A., Couzens, A. L., Antignano, F., Kuznetsova, E., Min, P. H., ... & Arrowsmith, C. H. (2013). Control of the hippo pathway by Set7-dependent methylation of Yap.Developmental cell, 26(2), 188-194.

4.Peng, C., Zhu, Y., Zhang, W., Liao, Q., Chen, Y., Zhao, X., ... & Yang, D. (2017). Regulation of the hippo-YAP pathway by glucose sensor O-GlcNAcylation. Molecular cell, 68(3), 591-604.

Source丨BioArt

Comment丨Yu Faxing (PI of Fudan University Institutes of Biomedical Sciences)

Editor in chief丨Jia Xu