Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer.

Dong Lin,Xin Dong,Colin C Collins,Francesco Crea,Anne Haegert,Rebecca Wu,Kendric Wang,Alexander W Wyatt,Peter W Gout,Yuzhuo Wang,Ladan Fazli,Antonio Hurtado-Coll,Hui Xue,Sonal Brahmbhatt,Martin E Gleave,Yuwei Wang,Robert H Bell

doi:10.18632/oncotarget.2809

Dong Lin, Xin Dong + Show 15 more

Open Access

https://doi.org/10.18632/oncotarget.2809

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Journal: Oncotarget	Publication Date: Dec 11, 2014
Citations: 74	License type: cc-by

Affiliation: University of British Columbia, BC Cancer Agency

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC.

Highlights

Prostate cancer (PCa) is the most common noncutaneous cancer and the second leading cause of death from cancer in North American men
We observed significantly increased DEK RNA expression in multiple Neuroendocrine prostate cancer (NEPC) models (LTL331R, LTL352 and LTL370) compared to adenocarcinoma models (Fig. 1A)
Among hormonal naïve prostate adenocarcinoma models, LTL331 showed higher expression of DEK compared to the other models (e.g., LTL311, LTL313B and LTL418) that did not give rise to NEPC after host castration (Fig. 1A)

Summary

Introduction

Prostate cancer (PCa) is the most common noncutaneous cancer and the second leading cause of death from cancer in North American men. Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of PCa, often leading to widespread metastasis and death within months of the initial diagnosis. It is characterized by small neuroendocrine (NE)-like cells which typically express NE markers such as chromogranin A (CHGA) and synaptophysin (SYP) and do not express androgen receptor (AR) or adenocarcinoma markers, such as prostate-specific antigen (PSA) [1, 2]. In recent years, accumulated biological and molecular evidence suggests that prostatic adenocarcinoma can undergo a NE transdifferentiation following androgen deprivation, and eventually progress to NEPC [4, 5]. Current treatment for NEPC provides only a marginal improvement in patients’ survival. New therapeutic targets and more effective treatments www.impactjournals.com/oncotarget are urgently needed to improve the management of the disease

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