Cerebral Cavernous Malformation 1 Determines YAP/TAZ Signaling-Dependent Metastatic Hallmarks of Prostate Cancer Cells

Abstract

Simple Summary Our analysis of cerebral cavernous malformation 1 (CCM1) expression and function reveals a candidate predictive biomarker for prostate cancer metastasis and provides evidence that CCM1 abnormality can be pathogenic in prostate cancer. In particular, the CCM1 regulation of metastasis appears as a common molecular event in metastatic prostate cancer cells arising from disparate genetic backgrounds. Enhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. We also demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. Our findings highlight the importance of CCM1-DDX5-YAP/TAZ signaling in the metastasis of prostate cancer cells.