Abstract
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.
Highlights
Prostate cancer (PCa) is one of the most common cancers in men worldwide and a leading cause of cancer mortality [1, 2]
LNCaP-SF cells derive from LNCaP cells and were isolated based on their ability to grow in the absence of androgen, representing an effective model of castration-resistant prostate cancer (CRPC) [26]
To clarify the mechanisms underlying the acquisition of androgen-independent cell growth, we first performed comprehensive gene expression profiling on parental LNCaP cells, and on LNCaP-SF cells transfected with scrambled Small interfering RNA (siRNA) or androgen receptor (AR)-targeting siRNA (AR knockdown) using an oligonucleotide microarray
Summary
Prostate cancer (PCa) is one of the most common cancers in men worldwide and a leading cause of cancer mortality [1, 2]. During the early stages of PCa, tumors are usually dependent on androgens for cellular function and growth; androgen deprivation therapy (ADT) is the first-line treatment for patients with locally advanced tumors and recurrent or metastatic disease. The majority of patients will progress to castrationresistant PCa (CRPC) within 2–3 years after initiation of ADT [3]. Amplification and/or overexpression of the androgen receptor (AR) gene is observed in approximately 30% of CRPCs [4, 5], and often sensitizes the AR to its antagonists, causing the latter to exhibit agonistic activity [6]. The androgen-AR signaling axis still plays a pivotal role in CRPC development, androgen-independent mechanisms contribute to disease progression [7]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.