RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer.

Ken-Ichi Takayama,Tetsuya Fujimura,Takashi Suzuki,Yukio Homma,Shuichi Tsutsumi,Tomohiko Urano,Hiroyuki Aburatani,Satoshi Inoue,Satoru Takahashi

doi:10.18632/oncotarget.2949

Abstract

Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. Our RUNX1 ChIP-seq analysis indicated that RUNX1 is recruited to AR binding sites by interacting with AR. In androgen-dependent cancer, loss of RUNX1 impairs AR-dependent transcription and cell growth. The RUNX1 promoter is bound by enhancer of zeste homolog 2 (EZH2) and is negatively regulated by histone H3 lysine 27 (K27) trimethylation. Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells. In clinical prostate cancer samples, the RUNX1 expression level is negatively associated with EZH2 and that RUNX1 loss correlated with poor prognosis. These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.

Highlights

Prostate cancer is the most frequently diagnosed cancer in men [1]
Using quantitative reverse transcriptase-PCR analysis, we found that RUNX1 is highly induced by R1881 10 nM treatment in LNCaP cells (Fig.1A)
RUNX1 has two distinct transcriptional start sites (TSSs: Promoter 1 and 2), and we found that promoter 2 is occupied with highly acetylated histone H3 by ChIP-seq analysis

Summary

Introduction

Prostate cancer is the most frequently diagnosed cancer in men [1]. Androgen and its cognate receptor, the androgen receptor (AR), are involved in prostate oncogenesis through the transcriptional regulation of target gene networks [2]. Androgen-deprivation therapy is a standard treatment for prostate cancer and efficiently inhibits the growth of androgen-dependent tumors. The majority of these cancers become refractory to hormone deprivation therapy and emerges as castration-resistant. Such castration-resistant prostate cancer (CRPC) is a significant clinical challenge, and investigation into the biologic mechanisms that contribute to tumor regrowth is of critical importance [1]. The first is enhancement of AR signaling caused by mutation, amplification of the AR gene or other mechanisms that allow for the activation of AR even with castration levels of serum testosterone [1, 8,9,10]. The other group uses www.impactjournals.com/oncotarget a mechanism to bypass AR signaling pathways [11], which allows cancer cells to survive in the absence of androgen-dependent or -independent AR activation. Cells that lack AR expression or had repressed AR signaling have been reported in large numbers of metastatic tumors derived from prostate cancer patients [12]

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Conclusion