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

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

doi:10.18632/oncotarget.2949

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

Oncotarget. 2015 Feb 10;6(4):2263-76. doi: 10.18632/oncotarget.2949.

Authors

Ken-ichi Takayama^{1

2}, Takashi Suzuki³, Shuichi Tsutsumi⁴, Tetsuya Fujimura⁵, Tomohiko Urano^{1

2}, Satoru Takahashi⁶, Yukio Homma⁵, Hiroyuki Aburatani⁴, Satoshi Inoue^{1

2

7}

Affiliations

¹ Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
² Department of Geriatric Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
³ Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
⁴ Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku, Tokyo, Japan.
⁵ Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
⁶ Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
⁷ Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Androgens / pharmacology
Blotting, Western
Cell Line, Tumor
Cell Proliferation / genetics
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism*
Dihydrotestosterone / pharmacology
Enhancer of Zeste Homolog 2 Protein
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
HEK293 Cells
Histones / metabolism
Humans
Immunohistochemistry
Male
Methylation
Middle Aged
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism*
Prognosis
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Protein Binding
RNA Interference
Receptors, Androgen / genetics
Receptors, Androgen / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Survival Analysis

Substances

Androgens
Core Binding Factor Alpha 2 Subunit
Histones
RUNX1 protein, human
Receptors, Androgen
Dihydrotestosterone
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2

Associated data

GEO/GSE62454
GEO/GSE62492