4.7 Review

New insights into the ambivalent role of YAP/TAZ in human cancers

Related references

Note: Only part of the references are listed.
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Summary: The Hippo signaling pathway inhibits the activity of the oncogenic YAP/TAZ-TEAD transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. Currently, three small molecule TEAD inhibitors are being tested in Phase I clinical trials.

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Summary: YAP is a key protein effector of the Hippo pathway, which controls cell growth, proliferation, and organ size. YAP regulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers are still unclear.

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Summary: Neutrophils, as an important component of tumor microenvironment, are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. In this study, tumor-specific neutrophils (tsNeus) were defined and characterized in gastric cancer (GC), revealing the essential role of YAP/TAZ-CD54 axis in tsNeus differentiation and antitumor activity. The relative amounts of CD54(+) tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Pharmacological enhancement of YAP activity selectively activated neutrophils to suppress refractory GC, providing a potential strategy for neutrophil-based antitumor therapeutics.

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YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth

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Summary: Hippo signaling inhibits the oncogenic potential of YAP/TAZ-TEAD transcriptional complex, restricting tumor growth. In AR-positive prostate cancer, YAP acts as a tumor suppressor by counteracting TEAD-mediated AR signaling. YAP competes with AR for TEAD binding, disrupting AR-TEAD interaction and preventing TEAD from promoting AR signaling. Targeting the Hippo signaling pathway may provide a therapeutic opportunity to treat therapy resistant AR variants-driven prostate cancer.

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Summary: This study reveals a previously unrecognized heterogeneity in the gene expression of Merkel cell carcinoma (MCC) and identifies an inverse correlation between neuroendocrine gene expression and the Hippo pathway transcription factors YAP1 and WWTR1. The expression of YAP1 or WWTR1 induces cell-cycle arrest in MCPyV-positive MCC cell lines through the TEAD-dependent repression of MCPyV LT. These findings shed light on the development of MCPyV-positive MCC and have implications for diagnosis and potential therapeutic interventions.

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Summary: The Hippo pathway, initially identified as a master regulator for cell proliferation and organ size control, has been found to also play important roles in development, tissue regeneration and homeostasis, inflammation, immunity, and cancer. YAP/TAZ, the downstream effectors of the Hippo pathway, act as coactivators and depend on other transcription factors to mediate their transcriptional outputs. This review provides an overview of the core components and regulations of the Hippo pathway in mammals, summarizes the identified transcriptional factors or partners responsible for the transcriptional output of YAP/TAZ in stem cells and differentiation, and discusses the potential applications and future directions based on these findings.

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Summary: This review discusses the role of the Hippo pathway in the tumorigenesis of breast cancer, oral cancer, rectal cancer, colloid cancer, and more. It analyzes the structural basis of the YAP/TAZ-TEAD complex and summarizes the targeting inhibitors within medicinal chemistry classification. The clinical status and current challenges of these drug candidates are also discussed, providing guidance for future development of inhibitors, particularly targeting the YAP/TAZ-TEAD complex.

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YAP-VGLL4 antagonism defines the major physiological function of the Hippo signaling effector YAP

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Summary: This study reveals that the essential role of YAP in liver and lung development can be bypassed by inactivation of the TEAD corepressor VGLL4, indicating that YAP's major physiological function is to antagonize VGLL4. The findings highlight the central importance of VGLL4-mediated transcriptional repression in regulating the Hippo pathway and provide insights into potential strategies for modulating Hippo signaling in cancer and regenerative medicine.

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Hippo signaling instructs ectopic but not normal organ growth

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Summary: YAP and TAZ are paralog transcriptional regulators that play roles in cell growth and differentiation by integrating mechanical, metabolic, and signaling inputs. They have both common and distinctive structural features and regulatory mechanisms, interacting with different transcriptional partners and controlling nonidentical transcriptional programs. Despite being considered functionally redundant in most literature, they have distinct or even contrasting roles in different contexts, implying significant implications for mechanistic and translational studies.

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YAP/TAZ and EZH2 synergize to impair tumor suppressor activity of TGFBR2 in non-small cell lung cancer

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Summary: YAP and TAZ play important roles in non-small cell lung cancer (NSCLC) by regulating the expression of miRNAs, including miR-25, 93, and 106b. They cooperate with EZH2 to transcriptionally repress TGFBR2 and other tumor suppressor genes, promoting lung tumorigenesis. These findings suggest YAP/TAZ and EZH2 as potential therapeutic targets for NSCLC treatment.

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WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma

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