E6AP promotes prostate cancer by reducing p27 expression.

Dinesh Raghu,Elena Takano,Scott Williams,Ygal Haupt,Siddhartha Deb,Ai-Leen Chan,Andrea Russo,Shahneen K Sandhu,Stephen B Fox,Sue Haupt,Piotr Jan Paul,Cristina Gamell,Christine Khoo,Giovanni Blandino,Twishi Gulati,Enzo Gallo

doi:10.18632/oncotarget.17224

Abstract

Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC. Down regulation of E6AP increases p27 expression and enhances its nuclear accumulation in PC. We demonstrate that E6AP regulates p27 expression by inhibiting its transcription in an E2F1-dependent manner. Concomitant knockdown of E6AP and p27 partially restores PC cell growth, supporting the contribution of p27 to the overall effect of E6AP on prostate tumorigenesis. Overall, we unravelled the E6AP-p27 axis as a new promoter of PC, exposing an attractive target for therapy through the restoration of tumor suppression.

Highlights

Prostate cancer (PC) is one of the leading causes of cancer death among men [1, 2]
The two independent Tissue microarray (TMA) represent patients from different stages of the disease; TMA1 contains biopsies sampled from 47 PC patients with Gleason score 6-9 and TMA2 contains 117 biopsies from PC patients with Gleason score 3-7
The analysis of the two TMA cohorts revealed that patients with high levels of E6-Associated Protein (E6AP) predominantly express low levels of p27 (Figure 1)

Summary

Introduction

Prostate cancer (PC) is one of the leading causes of cancer death among men [1, 2]. When not cured by local therapy, patients commonly progress to castration resistant PC (CRPC), which is a lethal form of the disease with limited treatment options. Promising PC treatment through tumor suppression restoration is emerging using proteasome inhibitors. Bortezomib [1, 2]) lack specificity and their poorlydefined, broad-spectrum impact, is often associated with significant side effects. Defining critical E3 ligases and their substrates along the PC-driving proteasomal degradation pathways will facilitate the development of more effective and selective therapies

Methods

Results

Conclusion