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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number100915
JournalTranslational Oncology
Volume14
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Androgen receptor (AR)
  • AR-V7
  • Castration-resistant prostate cancer (CRPC)
  • NUP210
  • SLC3A2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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