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

Sangryong Park,Jayoung Kim,Jaehong Kim,Eung-Gook Kim,Ho-Young Lee,Hansol Park,Young Seok Ju

doi:10.3390/cancers13051125

Abstract

Simple SummaryOur 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.

Highlights

We applied a larger dataset from the Prostate cancer (PCa) transcriptome atlas (PCTA), which we recently built using integrated bioinformatics analysis methods [26]
From the PCTA, we observed that cerebral cavernous malformation 1 (CCM1) levels were dramatically increased only in samples from patients with metastatic castration-resistant PCa (mCRPC) compared with those in primary prostate tissue and other stages of PCa (Figure 1C–D and Figure S1A–C)
CCM1 is an important regulator of the Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling and androgen receptor (AR) signaling in PCa cells by releasing YAP/TAZ signaling from DDX5-mediated suppression (Figure 7)

Summary

Introduction

PCa is a disease entity for which no effective therapies exist once it progresses to metastatic castration-resistant PCa (mCRPC), and clinically advanced PCa is responsible for more than 250,000 deaths worldwide annually [4,5]. Diverse sets of cancer hallmarks associated with aberrant functioning of the androgen receptor (AR), which is induced by androgen deprivation therapy (ADT), are the key driving forces behind the uncontrollable growth and metastasis of PCa and its transition into mCRPC [8,9,10]. The clinically heterogeneous, multifocal nature of PCa along with the late appearance of castration resistance (CR) and the resultant uncontrollable bone metastasis makes the disease frustratingly complex to investigate and treat [10,11]. Identifying the central molecular changes caused by current ADTbased therapeutic interventions, leading to the acquisition of uncontrollable metastasis, is critical for gaining important insights into key unmet needs, namely the improvement of diagnostic biomarkers and therapeutic interventions for mCRPC

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