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

Abstract

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

Keywords: Hippo signaling pathway; TEAD; YAP/TAZ; carcinogenesis; cell proliferation; chemoresistance; drug resistance; immunotherapy; neoplastic stem cells; tumor microenvironment.

Figure 1

Representation of the Hippo signaling pathway in humans. When the Hippo pathway is active (A), multiple signals stimulate the upstream components, which are NF2 and Mel. Subsequently, MST 1/2 protein and its substrate, LATS 1/2, are activated through phosphorylation processes and phosphorylate YAP/TAZ, which interacts with the 14-3-3 protein. Phosphorylation causes their cytoplasmic retention and generates ubiquitination processes mediated by proteasome degradation. When the Hippo pathway (B) is inactive, YAP/TAZ that are not phosphorylated translocate into the nucleus and form a transcription factor complex by binding to TEAD. This pathway regulates the transcription of genes involved in abnormal multiplication, chemoresistance and metastasis. YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; NF2: Neurofibrominin 2; MST: Mammalian sterile 20-like kinase; LATS: large tumor suppressor kinase; SAV1: Protein salvador homolog 1; MOB1: Mps1-binder-related; TEAD: Transcriptional enhanced associate domain.

Figure 2

YAP/TAZ signaling pathway in the tumor microenvironment. YAP/TAZ coactivators interact simultaneously with different elements of the TME causing (A) EMT during neoplastic progression. After the coupling of YAP/TAZ with the TEAD (A1), the complex is activated, and it induces the expression of target genes (A2) that promote the transition from the epithelial phenotype to the mesenchymal phenotype. (B) Angiogenesis. The presence of VEGF (B1) stimulates the activation of TAZ (B2) and the subsequent expression of genes (B3) that promote sustained angiogenesis of the blood vessels in the TME (B4). (C) Metabolic reprogramming. YAP/TAZ activation and the formation of the YAP/TAZ/TEAD complex (C1) promotes the expression of target genes that allow the cancer cell to acquire new metabolic pathways needed for its adaptation to the TME (C2). (D) Mechanotransduction. During tumor progression, the EMC adopts a rigid conformation (D1). YAP/TAZ act as sensors that detect EMC changes due to adhesion molecules (D2), promoting modifications in TME properties and intrinsic changes in tumor cells that allow them to survive in these conditions (D3). (E) Immunomodulation. When YAP/TAZ interact with immune cells (E1), they induce changes in the antitumoral phenotype of these cells promoting immune evasion, which leads to neoplastic progress (E2). YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; TME: Tumor Microenvironment, VEGF: Vascular Endothelial Growth Factor, EMT: Epithelial-Mesenchymal Transition, EMC: Extracellular Matrix, TAMs: Tumor-Associated Macrophages, TEAD: Transcriptional enhanced associate domain.

Figure 3

YAP/TAZ functions in metabolic heterogeneity. YAP/TAZ operate as nuclear and transcriptional mediators in different metabolic pathways during cancer, which results in increased tumor invasion, tumor progression and metastasis. (A) When YAP/TAZ activity is stimulated, the cell increases its glucose demand to promote glycolysis; the PFK1 enzyme is the coordinator of this interaction, considering that it regulates the stability of the union of the YAP/TAZ/TEAD complex in the cellular nucleus. (B) In terms of lipid metabolism, the release of free fatty acids induces the expression of the JCAD protein, while transcription of YAP occurs simultaneously through its dephosphorylation and union to the LATS2 domain. Consequently, translocation of YAP at the nuclear level, activation of the transcriptional module and transcription of target genes ensue. (C) The metabolism of mevalonate regulates the activity of YAP/TAZ through the production of geranyl pyrophosphate, which activates the Rho GTPase, which in turn dephosphorylates YAP/TAZ, promoting its accumulation in the cell nucleus and the transcription of its target genes. On the other hand, high levels of mevalonic acid boost the oncogenic activity of YAP /TAZ through the transcription of SREBP induced by the mutation of its cofactor p53. YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; PFK1: Phosphofructokinase 1; TEAD: Transcriptional enhanced associate domain; HBP: Hexosamine biosynthesis pathway; OGT: O-linked b-N-acetylglucosamine transferase; MG: Methylglyoxal; LATS: Large tumor suppressor kinase; HSP90: Heat shock protein 90; FZD4: Frizzled Class Receptor 4; JCAD: Junctional Cadherin 5 Associated; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; GGPP: Geranylgeranyl pyrophosphate; SREBP: Sterol regulatory element binding protein; CTGF: Connective tissue growth factor; CYR61: Cysteine-rich angiogenic inducer 61.

Figure 4

YAP/TAZ role in oncotherapy resistance. (A) Targeted therapy resistance. YAP/TAZ resistance to targeted therapy occurs mainly in EGFR and MAPK inhibitors, in non-small cell lung adenocarcinoma takes place thanks to the induction of high transcription levels of AXL. Meanwhile, YAP promotes resistance to MEK1/2 inhibition in neuroblastomas, with a hyperactive signaling of the RAS gene in cells treated with trametinib. Consequently, the overexpression of YAP produces transcription of genes that stimulate cell cycle entry, EMT, survival and cell death evasion, thus increasing resistance. (B) Chemotherapy resistance. The main mechanism used by YAP/TAZ to induce chemotherapy resistance is by binding to TEA domains, which produces the activation of the promoters of the Cyr61/CTGF oncogenes, causing resistance, evasion of apoptosis and hypoxia when overexpressed on the surface of tumor cells in breast cancer. In juxtaposition, the downregulation of MYPT1 produces the activation of the transcriptional module of the Hippo pathway, enhancing resistance to chemotherapy and the emergence of CSC phenotypes in ovarian cancer. (C) Immunotherapy resistance, PD-L1, CSF1-3, IL-6 and CXCL5 transcription create an enhanced immunosuppression activity by inhibiting monoclonal antibodies whose target is PD-L1. Subsequently, this phenomenon leads to the suppression of cytotoxic lymphocytes activity and a decrease in the production of cytokines resulting in T cell exhaustion. YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; TEAD: Transcriptional enhanced associate domain; MEK: Mitogen-activated protein kinase kinase; ZEB1: Zinc Finger E-Box Binding Homeobox 1; AP-1: activating protein-1; BRD4: Bromodomain Containing 4; CYR61: Cysteine-rich angiogenic inducer 61; MAPK: Mitogen-activated protein kinase; CXCR2: C-X-C Motif Chemokine Receptor 2; CXCL5: C-X-C Motif Chemokine Ligand 5; CSF1-3: Colony-stimulating factor 1–3; GRB2: Growth factor receptor-bound protein 2; TBK1: TANK Binding Kinase 1; NF-KB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-kinases; AKT: Protein kinase B; MTORC: mammalian target of rapamycin complex; AXL: AXL Receptor Tyrosine Kinase; EGFR: Epidermal growth factor receptor; EMT: Epithelial to mesenchymal transition; CTGF: Connective tissue growth factor; BCL-XL: B-cell lymphoma-extra-large gene; MYPT1: Myosin Phosphatase Target Subunit 1; IAP1: Apoptosis inhibitor 1; ABCC1: ATP Binding Cassette Subfamily C Member 1; ABCB1: ATP binding cassette subfamily B member 1; ABCG2: TP Binding Cassette Subfamily G Member 2; PD-L1: Programmed death-ligand 1; CSF: colony stimulating factor; IL-6: Interleukin 6; PD-1: Programmed cell death protein 1; ARG1: Arginase 1; CTLS: Cytotoxic T lymphocytes; TAMS: Tumor-associated macrophages; MDSCS: Myeloid-derived suppressor cells.