Abstract
Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
Highlights
Cancer is the second leading cause of death in the United States, with more than 1.6 million new cases estimated in 2014 [1]
We review the basic components of the Hippo pathway, the evidence that deregulation of this pathway leads to well-conserved tumor-like phenotypes in model systems, and the role of Hippo signaling in cancer and human disease
We find that despite a large array of upstream mechanisms that feed into the Hippo pathway, the evidence suggests that all mechanisms of deregulation result in the common activation of the transcription factors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)
Summary
Cancer is the second leading cause of death in the United States, with more than 1.6 million new cases estimated in 2014 [1]. Molecular alterations of hippo pathway components in human cancer In addition to work done in cell culture and model systems, a number of studies have shown that YAP/TAZ are activated in a wide range of human cancers, bolstering the evidence that deregulated Hippo signaling contributes to carcinogenesis. Other mechanisms of Hippo pathway alteration have been discovered in various human cancers, including copy-number changes, translocations, and epigenetic silencing, which could explain the observed YAP/TAZ activation without associated mutations in Hippo pathway genes. These Lats1/2 cancer mutations were shown to disrupt a number of Lats1/2 functions, including kinase activity, suppression of YAP activity, and tissue growth properties These data, along with the identified mutations, serve to bolster the evidence for Lats1/2 as tumor suppressor genes in a small subset of cancers [96]. These early advancements in targeting YAP have generated excitement over prospective new therapeutics to treat cancer and other disease
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