YAP/TAZ for cancer therapy: Opportunities and challenges (Review)

Abstract

YAP (Yes-associated protein) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif) are the main downstream effectors of the Hippo signaling pathway. This pathway is an evolutionally conserved signal cascade, which plays pivotal roles in organ size control and tumorigenesis from Drosophila to mammals. Functionally, when the Hippo pathway is activated, YAP and TAZ will be sequestered in the cytoplasm and degraded. Conversely, when the Hippo pathway is deactivated, YAP and TAZ will translocate into nucleus and promote transcription of downstream genes by forming complexes with transcription factors, such as transcriptional enhancer factors (TEF; also referred to as TEAD), runt-domain transcription factors (Runx) and others. Most of these transcription factors belong to growth promoting or apoptosis-inhibition genes. It has been reported that the deactivation of the Hippo pathway, as well as up-regulation of YAP and TAZ was observed in many human cancers with a high frequency, which suggests that the Hippo pathway may be a potent target for developing anticancer drugs. In this review, we provide an overview of the Hippo pathway and summarize recent advances with respect to the role of YAP and TAZ in Hippo signaling pathway and cancer development. Furthermore, we describe the opportunities and challenges for exploit YAP and TAZ as potential therapeutic targets in cancer.

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

“…For example, YAP specifically binds to ErbB4 and p73, whereas TAZ specifically binds to PPARc, Pax3, TBX5, and TTF-1. 57 In line with these results, we observed that FN1, COL1A1, and COL4A1 were specifically suppressed by silencing of YAP. Thus, it is likely that YAP, but not TAZ, can interact with a unique subset of transcription factors to induce the expression of FN1, COL1A1, and COL4A1 on TGF-b2 stimulation.…”

Rottlerin exhibits antitumor activity via down-regulation of TAZ in non-small cell lung cancer

“…A wealth of evidence has emerged that deactivation of the Hippo pathway and up-regulation of TAZ were observed in a wide spectrum of human cancers, suggesting that inactivation of TAZ could be a promising strategy for the treatment of cancers [39]. For example, microRNA-129-5p inhibited ovarian cancer cell proliferation and survival through suppression of TAZ [40].…”

Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP

“…YAP, first reported in 1994 as a binding partner of the SH3 domain of the Yes proto-oncogene product [12], is a key downstream effector of the Hippo signaling pathway. When the Hippo pathway is deactivated, YAP can translocate to the nucleus to activate gene expression by associating with a number of DNA-binding transcription factors, modulating diverse cellular functions, including proliferation, apoptosis, migration and differentiation [13, 14]. YAP is generally overexpressed in tumor tissues [15–17], and has been reported to modulate the epithelial-mesenchymal transition (EMT) and various pathways that are important for resistance to chemotherapy [18, 19].…”