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

Translational Oncology (Jan 2021)

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

Affiliations

Masahiro Sugiura: 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
Hiroaki Sato: 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
Atsushi Okabe: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan
Masaki Fukuyo: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan
Yasunobu Mano: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan
Ken-ichi Shinohara: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan
Bahityar Rahmutulla: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan
Kosuke Higuchi: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan
Maihulan Maimaiti: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Manato Kanesaka: 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
Yusuke Imamura: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Tomomi Furihata: Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan
Shinichi Sakamoto: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Akira Komiya: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Naohiko Anzai: Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan
Yoshikatsu Kanai: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan
Jun Luo: Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA
Tomohiko Ichikawa: Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Atsushi Kaneda: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan; Corresponding author.

Journal volume & issue: Vol. 14, no. 1
p. 100915

Abstract

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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.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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