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Transcriptional co-activators, YAP/TAZ, have attracted attention as promising targets in cancer therapy. YAP/TAZ are negatively regulated by the tumor suppressor Hippo pathway. In human cancers, YAP/TAZ are frequently hyperactivated as a consequence of dysregulation of the Hippo pathway. Mounting clinical evidence demonstrates a correlation between the activation of YAP/TAZ and poor prognosis. YAP/TAZ co-operate with transcription factors, TEADs, to induce epithelial-mesenchymal transition (EMT), and to cause resistance to drug treatment. It is reasoned that the inhibition of YAP/TAZ should improve prognosis in cancer patients. Researchers devote a great deal of effort to developing inhibitors of YAP/TAZ, and face many exciting opportunities as well as challenges. The aim of this special issue is to offer the basis for discussion about how to put the Hippo-targeted cancer therapy into practice. This paper is not intended to provide a comprehensive overview of the research on the Hippo pathway. All contributors were requested to write their manuscripts freely. Therefore, there is divergence in the styles of the presented papers. Some authors focus on their own research and introduce original findings as commentaries. Nevertheless, with twelve papers and reader-friendly introductions, the issue covers a significant part of the current achievements in this field. TEADs are the most important partners of YAP/TAZ. The interaction between YAP/TAZ and TEADs is regarded as a good candidate for cancer therapeutic intervention. Holden and Cunningham discuss how YAP/TAZ-TEAD interface is targeted [1]. Notably, although it is the prevailing view that transcription factors are unsuitable as drug targets, the identification of the lipid pocket in TEAD has drastically changed this view. Gibault et al. also introduce their own efforts toward the discovery of inhibitors of YAP-TEAD interaction by using virtual screening [2]. In the classical model, YAP/TAZ are regulated by the kinase cassette, MST-Sav1-MOB1-LATS. However, we now know that many other pathways regulate YAP/TAZ. Some of them work via the kinase cassette, while others directly modulate YAP/TAZ activity. Thus, YAP/TAZ can be inhibited in various ways. Warren et al. efficiently and conceptually review the possible methods [3]. Malignant mesothelioma (MM) is a representative cancer with dysregulation of the Hippo pathway. Sekido reviews how the Hippo pathway is disturbed in MM, and then discusses methods to suppress YAP/TAZ [4]. Reading these two reviews, we can obtain an overview of upstream strategies. Hardness is one of notable characters of cancer. YAP/TAZ respond to stiffness of extracellular matrixes (ECMs). Prevention of ECM stiffening is a rational choice to inhibit YAP/TAZ. Chakraborty and Hong highlight agrin, which enhances ECM stiffness, as a novel up-stream regulator of YAP in liver cancer; they discuss the potential therapeutic value of targeting agrin [5]. Rivas et al. propose WIP as a regulator of YAP/TAZ and discuss the role of WIP-YAP/TAZ in glioma with p53 mutations [6]. The expression levels of components of the Hippo pathway are regulated by E3 ligases. As one E3 ligase modulates more than one protein, it is not easy to predict the outcome of the targeting of E3 ligases. However, reading the review by Nguyen and Kugler, we understand that certain E3 ligases

Hippo Pathway in Cancer, towards the Realization of Hippo-Targeted Therapy