Circadian rhythm-related miR-6883-5p suppresses enzalutamide-resistant prostate cancer

Area of Science:

• Molecular Oncology
• Circadian Biology
• Cancer Therapeutics

Background:

• Prostate cancer (PCa) incidence is rising, with treatment-resistant castration-resistant prostate cancer (CRPC) posing a significant clinical challenge.
• Alterations in circadian rhythm genes are implicated in PCa progression and therapeutic resistance.

Purpose of the Study:

• To investigate the role of circadian rhythm gene PER1 and its associated microRNA, miR-6883-5p, in prostate cancer.
• To elucidate the regulatory mechanisms underlying miR-6883-5p's function in enzalutamide-resistant PCa.
• To explore the potential of targeting the circadian clock for CRPC treatment.

Main Methods:

• Quantitative real-time PCR and Western blotting to assess PER1 and miR-6883-5p expression in PCa cells and tissues.
• In vitro and in vivo functional assays to evaluate the impact of miR-6883-5p on enzalutamide-resistant PCa cell proliferation.
• Luciferase reporter assays and manipulation of transcription factor expression (BMAL1, CLOCK) to define regulatory pathways.

Main Results:

• PER1 and miR-6883-5p were significantly downregulated in PCa cells and clinical samples.
• Overexpression of miR-6883-5p suppressed enzalutamide-resistant PCa cell proliferation by directly targeting AR-V7.
• BMAL1 and CLOCK positively regulate PER1 and miR-6883-5p expression, while miR-6883-5p negatively regulates CLOCK, affecting the circadian transcription-translation feedback loop (TTFL).

Conclusions:

• A novel regulatory axis involving circadian components (PER1, BMAL1, CLOCK), miR-6883-5p, and AR-V7 is identified in PCa progression.
• miR-6883-5p acts as a tumor suppressor in enzalutamide-resistant PCa by targeting AR-V7.
• The circadian clock represents a promising therapeutic target for overcoming treatment resistance in CRPC.