New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

Abstract

The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.

Keywords: TAZ; TEAD; YAP; cancer therapy; gene regulation; metastasis.

Figure 1

Regulators of YAP/TAZ in the cytoplasm and the nucleus. In the cytoplasm, Hippo pathway components act as sensors and integrators of signaling inputs. In the nucleus, YAP/TAZ-TEAD and other cofactors act as effectors to control gene transcription. Various inputs, such as osmotic stress, heat shock, nutrient stress, mechanic stress, cell–cell contact, and cell polarity, are transmitted to YAP/TAZ-TEAD in Hippo-dependent and independent manners. Nutrient stress activates AMPK, which phosphorylates and inactivates YAP/TAZ; AMPK also phosphorylates and stabilizes AMOTL1, which in turn aids LATS-mediated YAP/TAZ dephosphorylation and inactivation. Heat shock promotes LATS dephosphorylation through HSP90 and PP5, while concurrently fostering LATS ubiquitination and degradation to activate YAP/TAZ. Osmotic stress induces transient nuclear translocation of YAP, a process facilitated by NLK, which phosphorylates YAP at Ser128, disrupting its interaction with 14-3-3. Cell adhesion molecules and their intracellular adaptors, such as FAT1, KIRREL1, NF2, AMOT, KIBRA, and Scribble, anchor MST and LATS to the plasma membrane to sustain their ability to inactivate YAP/TAZ. Stimulation of GPCRs can result in either activation or inhibition of YAP/TAZ, depending on the coupled G protein. Mechanic force, ECM stiffness, and shear stress exert on integrins and cause LATS1/2 inactivation through SRC, while SRC can also phosphorylate and activate YAP/TAZ, promoting their nuclear translocation. Cytoskeleton remodeling proteins, such as RhoA, are instrumental in LATS inactivation and cooperate with other signaling molecules including GNAQ, GPCR, and others. The STRIPAK complex is important in initiating MST-LATS activation through its multiple components, including STRN4, STK25, and PP2A. MAP4K is regulated by the STRIPAK complex and activates LATS1/2 in parallel to MST1/2 activation. TAO1/3 kinases promote LATS activation in both MST-dependent and -independent manners. NUAK2 acts as a YAP/TAZ activity enhancer by antagonizing LATS-mediated YAP/TAZ phosphorylation. Certain cytoplasmic lncRNAs, such as MAYA, SNHG9, and LncRIM, regulate Hippo pathway components by acting as scaffolds. The nuclear regulations of YAP/TAZ-TEAD include: (1) nuclear mechanical stress enhances the interaction of F-actin with the ARID1A-SWI/SNF complex, leading to the liberation and activation of YAP/TAZ; (2) YAP, TAZ, and their fusion proteins can undergo phase separation, facilitating their transcriptional activity by chromatin remodeling; (3) VGLL family members sequester TEAD to inhibit YAP/TAZ-TEAD binding, restricting transcriptional activity; and (4) the nuclear lncRNA MALAT1 binds and sequesters TEAD to block its interaction with YAP and target gene promoters. Other signaling pathways, such as RAS-RAF-MAPK, TGF-β–SMAD, GPCR, integrin, and Wnt pathways, interact with the Hippo pathway to exert positive or negative effects on the activity of YAP/TAZ.

Figure 2

Regulation modes of YAP/TAZ on ERα. (a) LATS1/2 kinases interact with ERα, targeting it for ubiquitination and proteasomal degradation by the DCAF1 complex. In the absence of LATS1/2, ERα and YAP/TAZ are stabilized. (b) YAP-TEAD bind to a subset of ERα-bound enhancers independently of TEAD’s DNA binding ability, through a combination of factors including enhancer RNA (eRNA), the chromatin modifier FOXA1, and other cofactors, leading to H3K4 methylation and H3K27 acylation. (c) TEAD physically associates with ERα to enhance its occupancy of promoters/enhancers, while YAP disrupts this interaction, thereby reducing the occupancy of target promoters/enhancers by ERα and promoting ERα’s proteasomal degradation. (d) YAP activation stimulates the expression of VGLL3, which in turn recruits the nuclear receptor corepressor 2 (NCOR2) to the super-enhancer of the ESR1 gene, leading to decreased ERα expression.

Figure 3

Roles of YAP/TAZ in metastasis, tumor immunity, and therapeutic response. (a) YAP/TAZ-TEAD-mediated regulation of tumor dormancy, metastatic relapse, and organ tropism. (1) Astrocyte-deposited laminin-211 binds the DAG1 receptor on DTCs, retaining YAP in the cytoplasm, thereby inducing cellular quiescence. (2) The lncRNA MAYA facilitates MST1 methylation and inactivation by recruiting LLGL2 and NSUN6, which leads to increased CTGF expression and secretion, promoting osteoclast differentiation and the vicious circle of bone metastasis. (3) Fatty liver conditions can boost the production of hepatocyte-derived extracellular vesicles (EVs). These EVs contain a group of microRNAs to suppress LATS, thereby enhancing YAP activity and upregulating the YAP target CYR61 in CRC cells, which nurtures an immunosuppressive milieu conducive to CRC liver metastasis. (4) Lymph nodes can selectively activate YAP in melanoma cells within their microenvironment, characterized by high fatty acid and bile acid content. This activation redirects tumor cell metabolism towards fatty acid oxidation, thereby promoting lymph node metastasis. (b) YAP/TAZ leads to immune suppression in cancer by promoting PD-L1 expression in tumor cells, promoting the differentiation and functions of immunosuppressive cells (e.g., Tregs, TAMs, and MDSCs), and inhibiting CD8+ T cell function. (c) The integration of approaches such as synthetic lethality, transcriptional addiction, and modulation of bypass pathways could produce a synergistic therapeutic impact.

Figure 4

The tumor-suppressing role of YAP/TAZ. Summary of recent research on the tumor-suppressing role of YAP/TAZ and the underlying mechanisms.