A Multifunctional LNA Oligonucleotide-Based Strategy Blocks AR Expression and Transactivation Activity in PCa Cells

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• The androgen receptor (AR) is crucial for prostate cancer (PCa) progression by activating androgen-induced genes.
• Inhibiting AR-mediated transcription is a key strategy to control PCa growth and metastasis.

Purpose of the Study:

• To develop novel therapeutic molecules targeting the androgen receptor (AR) for prostate cancer (PCa) treatment.
• To investigate the potential of splice-switching oligonucleotides (SSOs) to modulate AR splicing and function.

Main Methods:

• Utilized tailor-made splice-switching locked nucleic acid (LNA) oligonucleotides (SSOs) to alter AR precursor mRNA splicing.
• Introduced premature stop codons to destabilize AR transcripts and favored the production of the AR45 isoform.
• Screened SSOs for dual function: silencing full-length AR and promoting the inhibitory AR45 isoform.

Main Results:

• SSOs successfully redirected AR pre-mRNA splicing, leading to transcript destabilization and reduced full-length AR.
• Selected SSOs promoted the expression of AR45, an AR isoform that antagonizes AR activity.
• The developed SSOs effectively silenced AR expression and modulated AR-responsive genes.

Conclusions:

• A bi-functional SSO strategy offers a novel therapeutic approach for prostate cancer (PCa) by targeting AR.
• This approach simultaneously silences AR and promotes an inhibitory AR isoform (AR45).
• The strategy is potentially adaptable for other therapies requiring gene silencing and isoform modulation.