A YAP/TAZ-CDC6 Axis Initiates and Maintains Malignant Transformation
David Nduru1, Yudai Ohta1,2, Akihiro Nita2
1Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Science
|November 29, 2025
Summary
The Hippo pathway proteins YAP and TAZ drive cancer by activating CDC6, a gene crucial for cell division. Targeting this YAP/TAZ-CDC6 axis could offer new cancer therapies.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Signaling
Background:
- Malignant transformation requires cells to gain proliferative advantages, often via dysregulated signaling pathways.
- The Hippo pathway effectors YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) are key regulators of cell proliferation, and their aberrant activation is implicated in tumorigenesis.
- The precise molecular mechanisms by which YAP and TAZ sustain malignant transformation are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which YAP and TAZ promote and maintain malignant transformation.
- To identify key downstream targets of YAP and TAZ involved in sustaining the transformed phenotype.
- To explore the therapeutic potential of targeting the YAP/TAZ pathway in cancer.
Main Methods:
- Utilized an in vitro transformation model with immortalized mouse embryonic fibroblasts (iMEFs) expressing active YAP or TAZ.
- Performed transcriptomic profiling to identify YAP/TAZ-regulated genes.
- Conducted functional assays to assess the role of identified targets in malignant transformation.
- Analyzed The Cancer Genome Atlas (TCGA) datasets for correlations between YAP/TAZ activity and target gene expression in human cancers.
Main Results:
- Constitutive expression of YAP or TAZ was sufficient to induce malignant transformation in iMEFs, and their removal reversed this phenotype.
- Transcriptomic analysis revealed a 17-gene signature upregulated by YAP, enriched in cell cycle genes, with CDC6 (cell division cycle 6) identified as a critical target.
- Depletion of CDC6 impaired YAP/TAZ-induced anchorage-independent growth, a hallmark of transformation.
- TCGA data analysis showed elevated CDC6 expression in human tumors with high YAP/TAZ activity, correlating positively with YAP/TAZ expression.
Conclusions:
- The YAP/TAZ-CDC6 axis is a conserved mechanism driving malignant transformation.
- YAP and TAZ are necessary for both the initiation and maintenance of the transformed state.
- The YAP/TAZ-CDC6 pathway represents a promising therapeutic target for a wide range of cancers.
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