A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate...

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• MicroRNA-346 (miR-346) activates Androgen Receptor (AR) signaling and associates with DNA damage response (DDR) transcripts in prostate cancer (PC).
• The role of miR-346 in DNA damage and its therapeutic potential in PC remain to be fully elucidated.

Purpose of the Study:

• To investigate the impact of miR-346 on DNA damage in prostate cancer cells.
• To explore the therapeutic potential of modulating miR-346 in prostate cancer.

Main Methods:

• Employed RNA-immunoprecipitation (RIP), RNA-sequencing (RNA-seq), RNA-fluorescence in situ hybridization (FISH), DNA fiber assays, and in vivo xenograft studies.
• Utilized a novel INDUCE-seq method for single nucleotide-resolution genome-wide mapping of DNA breaks.
• Investigated the interaction between miR-346, NORAD, and PUM2, and assessed drug sensitivity and tumor regression.

Main Results:

• miR-346 induces rapid and extensive DNA damage in PC cells via transcriptional hyperactivation, R-loop formation, and replication stress.
• miR-346 disrupts the interaction between lncRNA NORAD and PUM2, leading to increased turnover of DDR transcripts and promoting DNA damage.
• miR-346 sensitizes PC cells to DNA-damaging agents and induces tumor regression in vivo, suggesting therapeutic potential.

Conclusions:

• The balance between miR-346 and NORAD is critical for regulating DNA damage and repair in prostate cancer.
• miR-346 holds therapeutic promise, particularly in advanced PC with decreased NORAD and in transcriptionally hyperactive cancer cells.