Suppression of prostate tumor cell survival by antisense oligonucleotide-mediated inhibition of AR-V7 mRNA synthesis

• Published in: Oncogene Vol. 38; no. 19; pp. 3696 - 3709
• Main Authors: Luna Velez, Maria V, Verhaegh, Gerald W, Smit, Frank, Sedelaar, J P Michiel, Schalken, Jack A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2019; Nature Publishing Group UK
• Subjects: Androgen receptors; Androgens; Antisense oligonucleotides; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Care and treatment; Castration; Cell culture; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell proliferation; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Codons; Enhancer Elements, Genetic; Enzalutamide; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genes; Genetic aspects; Humans; Kinases; Male; Messenger RNA; Nonsense mutation; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Serine-Threonine Kinases - genetics; Receptors, Androgen - genetics; Risk factors; RNA; RNA, Messenger - biosynthesis; Splicing; Stop codon; Tumors; Ubiquitin-Conjugating Enzymes - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0696-7

One of the mechanisms by which advanced prostate cancer develops resistance to androgen deprivation therapy is the elevated expression of C-terminally truncated androgen receptor (AR) variants. These variants, such as AR-V7, originate from aberrant splicing of the AR pre-mRNA and the inclusion of a cryptic exon containing a premature stop codon in the mRNA. The resulting loss of the ligand-binding domain allows AR-V7 to act as a constitutively active transcription factor. Here, we designed two antisense oligonucleotides (AONs) directed against cryptic splicing signals within the AR pre-mRNA. These two AONs, AON-ISE and AON-ESE, demonstrated high efficiency in silencing AR-V7 splicing without affecting full-length AR expression. The subsequent downregulation of AR-V7-target gene UBE2C was accompanied by inhibition of androgen-independent cell proliferation and induction of apoptosis in castration-resistant prostate cancer (CRPC)-derived cell line models 22Rv1, DuCaP, and VCaP. Our results show that splicing-directed AONs can efficiently prevent expression of AR-V7, providing an attractive new therapeutic option for the treatment of CRPC.