Prostate cancer (PCa) is the most common cancer among men in the United States and a leading cause of cancer-related deaths, especially in cases resistant to androgen deprivation therapy (ADT) like enzalutamide.

While enzalutamide therapy can extend survival in castration-resistant prostate cancer (CRPC) by an average of 4.8 months, many patients develop resistance within one to two years, with the underlying mechanisms still not fully understood.

The treatment with enzalutamide has been shown to increase the expression of circCDR1-AS, which is associated with enhanced resistance to the drug in CRPC cell lines.

Moreover, suppressing circCDR1-AS in resistant cells has been found to increase sensitivity to enzalutamide, confirming its pivotal role in mediating resistance.

The study reveals that enzalutamide and androgen receptor (AR) signaling can transcriptionally regulate circCDR1-AS by binding to the promoter region of its host gene, CDR1.

Focusing on circular RNAs (circRNAs), particularly circCDR1-AS, the research suggests that these molecules may modulate cancer stem cell (CSC) traits and influence enzalutamide sensitivity through various regulatory pathways involving miRNAs.

A significant interaction was noted between circCDR1-AS and miR-1290, where the expression of miR-1290 was inversely related to circCDR1-AS levels, impacting CSC characteristics.

Furthermore, BMP4, a gene related to CSCs, was influenced by miR-1290 levels, indicating a complex regulatory network involving circCDR1-AS, AR signaling, and miRNA interactions that collectively affect enzalutamide resistance in prostate cancer.

Research highlights the importance of prostate cancer stem cells (CSCs) in developing resistance to ADT, with specific CSC markers such as CD44, CD133, and BMP4 playing significant roles in tumor progression.

Alterations in CSC traits due to circCDR1-AS expression were confirmed by increased expression of CSC biomarkers and enhanced sphere-forming capacity in resistant cells.