A YAP / TAZ – CDC6 Axis Initiates and Maintains Malignant Transformation

Malignant transformation involves the acquisition of proliferative advantages by cells, often through the dysregulation of key signaling pathways. The Hippo pathway effectors YAP and TAZ are well‐established regulators of cell proliferation, and their aberrant activation is linked to tumorigenesis in various cancers. However, the molecular mechanisms by which YAP and TAZ sustain malignant transformation remain unclear. In this study, we employed an in vitro transformation model using immortalized mouse embryonic fibroblasts (iMEFs) constitutively expressing active YAP or TAZ. We demonstrated that YAP or TAZ hyperactivation is sufficient to induce malignant transformation, and that the removal of these proteins reverses the transformed phenotype, indicating their necessity for both tumor initiation and maintenance. Transcriptomic profiling identified a 17‐gene signature specifically upregulated by YAP, which was enriched in cell cycle–related genes. Among these, CDC6, a DNA replication licensing factor, emerged as a critical target of YAP and TAZ. Functional assays revealed that CDC6 depletion impaired YAP/TAZ‐induced anchorage‐independent growth. Moreover, analysis of The Cancer Genome Atlas (TCGA) datasets showed elevated CDC6 expression across multiple human tumors with high YAP and TAZ activity, and a strong positive correlation between CDC6 and YAP/TAZ expression. These findings highlight that the conserved YAP/TAZ–CDC6 axes are key drivers of malignant transformation and underscore their potential as therapeutic targets across diverse cancer types.