Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth
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Ryuji Yamamoto1, Tsuyoshi Osawa1, Yusuke Sasaki1, Shogo Yamamoto2, Motonobu Anai1, Kouji Izumi3, Yoshihiro Matsumura4, Juro Sakai4,5, Hiroyuki Aburatani2, Atsushi Mizokami3, Tatsuhiko Kodama1 and Toshiya Tanaka1
1Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
2Division of Genome Science, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
3Department of Integrative Cancer Therapy and Urology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
4Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
5Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
Toshiya Tanaka, email: [email protected]
Keywords: CRPC; neuroendocrine prostate cancer; p54nrb/NONO; RNA splicing; EPHA6
Abbreviations: PCa-prostate cancer, CRPC-castration-resistant prostate cancer, LNCaP-SF-LNCaP steroid free
Received: August 24, 2017 Accepted: January 02, 2018 Published: January 08, 2018
The non-POU domain-containing octamer binding protein p54nrb/NONO is a multifunctional nuclear protein involved in RNA splicing, processing, and transcriptional regulation of nuclear hormone receptors. Through chromosome copy number analysis via whole-exome sequencing, we revealed amplification of the chromosome Xq11.22-q21.33 locus containing the androgen receptor (AR) and NONO genes in androgen-independent, castration-resistant prostate cancer (CRPC)-like LNCaP-SF cells. Moreover, NONO was frequently amplified and overexpressed in patients with CRPC. RNA sequencing data revealed that a truncated ephrin type-A receptor 6 (EPHA6) splice variant (EPHA6-001) was overexpressed in LNCaP-SF cells, and knockdown of NONO or EPHA6-001 prevented EPHA6-001 expression and reduced proliferation and invasion by LNCaP-SF cells grown under androgen deprivation conditions. Growth inhibition and differential splicing of EPHA6 mRNA by p54nrb/NONO were confirmed in gene silencing experiments in 22Rv1 PCa cells. Importantly, NONO knockdown in LNCaP-SF cells led to reduced tumor growth in castrated mice. These findings indicate that p54nrb/NONO is amplified and overexpressed in CRPC cells and clinical samples, and facilitates CRPC growth by mediating aberrant EPHA6 splicing. We therefore propose that p54nrb/NONO constitutes a novel and attractive therapeutic target for CRPC.
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