YAP/TAZ at the Roots of Cancer

Abstract

YAP and TAZ are highly related transcriptional regulators pervasively activated in human malignancies. Recent work indicates that, remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, chemoresistance, and metastasis. YAP/TAZ are sensors of the structural and mechanical features of the cell microenvironment. A number of cancer-associated extrinsic and intrinsic cues conspire to overrule the YAP-inhibiting microenvironment of normal tissues, including changes in mechanotransduction, inflammation, oncogenic signaling, and regulation of the Hippo pathway. Addiction to YAP/TAZ thus potentially represents a central cancer vulnerability that may be exploited therapeutically.

YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

“…Up-regulation of gp130 connects YAP and its downstream targets to localized inflammatory signals that are provided by IL-6 family members. Our findings re-enforce the important oncogenic function of YAP (21) and explain the basis for its frequent activation in CRC and possibly other epithelial tumors that are devoid of mutations that disrupt Hippo signaling. Indeed, the SFK-YAP module also functions in skin cancer (33).…”

“…Other signaling pathways responsible for epithelial survival and injury repair rely on the key transcriptional regulators STAT3 and YAP (16,17). Although the role of STAT3 in regeneration and colorectal tumorigenesis is unequivocal (18,19), it is still debated whether YAP is a tumor suppressor (20) or an oncogenic driver (21). Here we show that Src, YAP, STAT3, and Notch are coordinately activated in mouse APC-deficient intestinal organoids and colonic tumors and in 64% of human CRC specimens.…”

“…Indeed, the SFK-YAP module also functions in skin cancer (33). YAP up-regulation in epithelial cancers is also known to account for acquired drug resistance (21), but the underlying mechanisms were not reported. Our results indicate that at least in CRC, the major mechanism responsible for sustained YAP activation is the YAP-IL-6ST-SFK autoregulatory loop described above.…”

A Novel NHERF1 Mutation in Human Breast Cancer and Effects on Malignant Progression

“…YAP was first identified by its ability to associate with the SH3 domain of YES and SRC protein tyrosine kinases. When YAP is located in the nucleus, it acts as a transcriptional co-activator in cellular proliferation and other cancer-related malignant pathway (36). In this study, we found NHERF1 A190D mutation also appears to affect YAP function.…”

YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC

“…Despite numerous studies focusing on the genetic alterations associated with gastric cancer, our knowledge is limited about the signaling pathways that drive malignant transformation (2)(3)(4)(5)(6). The Hippo signaling pathway (also known as Hippo-YAP/TAZ signaling) is a growth control and tumor suppressor pathway associated with carcinogenesis, regeneration, and metabolism (7)(8)(9)(10)(11). In this pathway, the core kinases MST1/2 and LATS1/2 negatively regulate the effector molecules YAP and TAZ.…”