Identification of AR-V7 downstream genes commonly targeted by AR/AR-V7 and specifically targeted by AR-V7 in castration resistant prostate cancer

Masahiro Sugiura; Hiroaki Sato; Atsushi Okabe; Masaki Fukuyo; Yasunobu Mano; Ken-Ichi Shinohara; Bahityar Rahmutulla; Kosuke Higuchi; Maihulan Maimaiti; Manato Kanesaka; Yusuke Imamura; Tomomi Furihata; Shinichi Sakamoto; Akira Komiya; Naohiko Anzai; Yoshikatsu Kanai; Jun Luo; Tomohiko Ichikawa; Atsushi Kaneda

doi:10.1016/j.tranon.2020.100915

Identification of AR-V7 downstream genes commonly targeted by AR/AR-V7 and specifically targeted by AR-V7 in castration resistant prostate cancer

Transl Oncol. 2021 Jan;14(1):100915. doi: 10.1016/j.tranon.2020.100915. Epub 2020 Oct 20.

Authors

Masahiro Sugiura¹, Hiroaki Sato¹, Atsushi Okabe², Masaki Fukuyo², Yasunobu Mano², Ken-Ichi Shinohara², Bahityar Rahmutulla², Kosuke Higuchi³, Maihulan Maimaiti⁴, Manato Kanesaka¹, Yusuke Imamura⁴, Tomomi Furihata⁵, Shinichi Sakamoto⁴, Akira Komiya⁴, Naohiko Anzai⁵, Yoshikatsu Kanai⁶, Jun Luo⁷, Tomohiko Ichikawa⁴, Atsushi Kaneda⁸

Affiliations

¹ Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan.
² Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan.
³ Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁴ Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁵ Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁶ Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁷ Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan. Electronic address: kaneda@chiba-u.jp.

Abstract

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) under androgen deprivation therapy, by mechanisms e.g. expression of androgen receptor (AR) splice variant-7 (AR-V7). Here we conducted comprehensive epigenome and transcriptome analyses comparing LNCaP, primary PC cells, and LNCaP95, AR-V7-expressing CRPC cells derived from LNCaP. Of 399 AR-V7 target regions identified through ChIP-seq analysis, 377 could be commonly targeted by hormone-stimulated AR, and 22 were specifically targeted by AR-V7. Among genes neighboring to these AR-V7 target regions, 78 genes were highly expressed in LNCaP95, while AR-V7 knockdown led to significant repression of these genes and suppression of growth of LNCaP95. Of the 78 AR-V7 target genes, 74 were common AR/AR-V7 target genes and 4 were specific AR-V7 target genes; their most suppressed genes by AR-V7 knockdown were NUP210 and SLC3A2, respectively, and underwent subsequent analyses. NUP210 and SLC3A2 were significantly upregulated in clinical CRPC tissues, and their knockdown resulted in significant suppression of cellular growth of LNCaP95 through apoptosis and growth arrest. Collectively, AR-V7 contributes to CRPC proliferation by activating both common AR/AR-V7 target and specific AR-V7 target, e.g. NUP210 and SLC3A2.

Keywords: AR-V7; Androgen receptor (AR); Castration-resistant prostate cancer (CRPC); NUP210; SLC3A2.