Overexpression of p54/NONO induces differential splicing and contributes to castration-resistant prostate cancer growth.

The non-POU domain-containing octamer binding protein p54/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 () and genes in androgen-independent, castration-resistant prostate cancer (CRPC)-like LNCaP-SF cells. Moreover, was frequently amplified and overexpressed in patients with CRPC. RNA sequencing data revealed that a truncated ephrin type-A receptor 6 () splice variant () was overexpressed in LNCaP-SF cells, and knockdown of or prevented expression and reduced proliferation and invasion by LNCaP-SF cells grown under androgen deprivation conditions. Growth inhibition and differential splicing of mRNA by p54/NONO were confirmed in gene silencing experiments in 22Rv1 PCa cells. Importantly, knockdown in LNCaP-SF cells led to reduced tumor growth in castrated mice. These findings indicate that p54/NONO is amplified and overexpressed in CRPC cells and clinical samples, and facilitates CRPC growth by mediating aberrant splicing. We therefore propose that p54/NONO constitutes a novel and attractive therapeutic target for CRPC.