Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers

Yan Zhang,Ying Liu,Huanxing Han,Mohit Hulsurkar,Wangjun Liao,Michael Ittmann,Martin Gleave,Ting Zhou,Dayong Zheng,Wenliang Li,Long Shao,Ning Su,Feng Xu,Haiping Song,Hongbo Wang,Zheng Wang

doi:10.1038/s41467-018-06177-2

Abstract

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

Highlights

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgendeprivation therapy (ADT) is rising
To determine whether androgen deprivation therapy (ADT) activates CREB, we found that enzalutamide (MDV3100) treatment leads to enhanced CREB activation in AR-positive LNCaP and VCaP cells, which is reversed by androgen DHT (Fig. 1a)
NE1.3 was derived from LNCaP cells upon long term culturing in charcoal stripped serum (CSS) medium that deprives hormone and mimics ADT24. 144-13 cells were derived from NEPC patient-derived xenograft (PDX) MDA PCA-144-1325

Summary

Introduction

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgendeprivation therapy (ADT) is rising. We elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression. We and others have previously shown that ADT leads to activation of CREB, which in turn promotes neuroendocrine differentiation (NED) of prostate cancer cells[7,8]. In AR-positive prostate cancer cells, CREB-binding protein (CBP), a histone acetyltransferase, has been shown to act as an AR coactivator in transcriptional activation of AR target genes[9] It is still largely unclear how CREB activation promotes AR-indifferent NEPC. Overexpression of EZH2 in prostate cancer cells is known to promote prostate cancer cell proliferation and migration (review[11]) It remains incompletely understood whether and how EZH2 directly contributes to NED, and what biological processes are responsible for elevated PRC2 activity in NEPC cells[6,16]. Confirmation and characterization of an EZH2-TSP1 relationship was still lacking

Methods

Results

Conclusion