Emerging Principles in the Transcriptional Control by YAP and TAZ

Abstract

Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers

“…Another variation of the GAL4-based assay is that it can be used to isolate compounds that specifically inhibit YAP-transcriptional activity. Since YAP can also interact with transcription factors other than TEAD1–4, TEAD inhibitors may not completely block YAP activity [ 2 , 3 ]. It is, therefore, desirable to develop compounds to specifically inhibit interaction of the YAP-transcriptional activation domain (TAD) with its cognate partners.…”

“…Phosphorylated YAP/TAZ becomes sequestered in the cytoplasm by interacting with 14-3-3 proteins. Hypo/unphosphorylated YAP/TAZ translocate into the nucleus and associate with TEAD1-4 transcription factors to regulate the expression of a large number of target genes [ 2 , 3 ]. Many of the YAP target genes encode matricellular proteins that promote cell proliferation.…”

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

“…Since YAP/TAZ does not have binding domains to the DNA molecule, it must form complexes with DNA-binding proteins to regulate gene expression. Various transcriptional factors have been identified to interact with YAP/TAZ, such as Activator protein-1 (AP-1), E2F, MYC, myocardin-related transcription factor/serum response factor (MRTF/SRF), RUNX, Transcriptional Repressor GATA Binding 1 (TRPS1), Zinc Finger E-Box Binding Homeobox 1 (ZEB1), SNAIL, SLUG, Notch Intracellular Domain/Recombination Signal-Binding Protein for Ig Kappa J region (NICD/RBPJ), among several others [ 16 ]. However, the TEAD appears to be the most critical partner for transactivation and growth promotion [ 28 ].…”

“…Abnormal nuclear expression of YAP/TAZ proteins is associated with poor prognosis of different types of cancer [ 11 , 12 , 13 , 14 , 15 ]. In addition, YAP/TAZ can associate with other transcription factors leading to cell remodelling, proliferation, and invasion [ 16 ]. Therefore, this review aims to summarize the role of YAP/TAZ pathways in carcinogenesis and the tumor microenvironment and highlight the importance of potential as therapeutic alternatives involving this signaling pathway.…”

Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

“…regulation of the YAP/TEAD-dependent reporter gene activity, activation of YAP/TEAD target genes, regulation of YAP/TEAD interaction). However, although the YAP-regulated gene expression is mainly accomplished through the DNA binding mediated by TEAD family members, increasing evidence of additional transcriptional partners of YAP and of their role in triggering cell typeand context-speci c cellular responses has been collected (54). Therefore, the possible regulation by ERK5 of other YAP-containing transcriptional complexes cannot be excluded.…”