Minor intron splicing is critical for survival of lethal prostate cancer

Area of Science:

• Molecular Biology
• Oncology
• RNA Biology

Background:

• The minor spliceosome (MiS) is essential for expressing proteins from minor intron-containing genes (MIGs).
• MIGs play critical roles in cell-cycle regulation, DNA repair, and MAP-kinase signaling pathways.
• MiS activity is regulated by androgen receptor signaling and U6atac RNA levels, increasing in advanced prostate cancer (PCa).

Purpose of the Study:

• To investigate the role of MIGs and MiS in cancer, using prostate cancer as a model.
• To evaluate the therapeutic potential of inhibiting MiS in advanced, therapy-resistant PCa.

Main Methods:

• Utilized in vitro PCa models to study MiS function.
• Employed small interfering RNA (siU6atac) to inhibit MiS activity.
• Assessed tumor burden reduction and splicing of the REST factor.

Main Results:

• Inhibition of MiS by siU6atac led to aberrant minor intron splicing and cell-cycle G1 arrest in PCa cells.
• siU6atac demonstrated approximately 50% greater efficiency in reducing tumor burden compared to antiandrogen therapy in advanced therapy-resistant PCa models.
• siU6atac disrupted the splicing of the RE1-silencing factor (REST), a critical factor in lethal PCa.

Conclusions:

• The minor spliceosome (MiS) represents a significant vulnerability in lethal prostate cancer.
• Targeting MiS, potentially through U6atac inhibition, offers a promising therapeutic strategy for advanced and therapy-resistant prostate cancer.
• MiS may also be a viable therapeutic target in other cancer types.