E6AP Promotes a Metastatic Phenotype in Prostate Cancer

Highlights

• Elevated E6AP levels in primary PC in men correlate with regional metastasis

• Elevated E6AP levels promote mesenchymal features and migration potential

• E6AP promotes a metastatic phenotype by reducing NDRG1 expression levels

• Pharmacological upregulation of NDRG1 suppresses E6AP-induced cell migration

Summary

Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.