Abstract
SummaryAlthough 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.
Highlights
Metastatic prostate cancer (PC) is a major health problem that results in death in two-thirds of its patients within five years (Siegel et al, 2018)
We demonstrate that high levels of E6-associated protein (E6AP) in primary PC are often associated with loco-regional metastasis
The great majority (81%) of lymph node positive patients expressed high levels of E6AP (Figure 1B). These correlative clinical findings suggest a role for E6AP in the promotion of metastasis and raise the possibility that E6AP may serve as a predictive biomarker for aggressive PC phenotype
Summary
Metastatic prostate cancer (PC) is a major health problem that results in death in two-thirds of its patients within five years (Siegel et al, 2018). The majority of prostate cancer patients have an initial response to androgen-deprivation therapy, most men with metastases develop resistance to primary hormone therapies: a condition termed metastatic castration-resistant PC. In addition to its E3 ligase activity, E6AP can act as a transcription co-factor, as demonstrated by its role in regulating the transcriptional activities of nuclear hormone receptors (Nawaz et al, 1999; Raghu et al, 2017) and of E2F-1, as we recently showed (Gamell et al, 2017a; Raghu et al, 2017)
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