N6-methyladenosine-modified circQKI inhibits prostate cancer docetaxel-sensitivity via miR-188-3p/Beclin-1 pathway.

BACKGROUND: Docetaxel (DTX) is used in the first-line chemotherapy for advanced castration-resistant prostate cancer (CRPC), but resistance remains a major clinical challenge. Circular RNAs (circRNAs) play critical roles in DTX resistance. This study aimed to investigate the mechanism of a novel circRNA, circQKI, in DTX resistance and its regulatory network in CRPC.

METHODS: DTX-resistant cell lines (PC3/DR and 22RV1/DR) were established, and circQKI's circular structure was validated by Sanger sequencing. CircQKI expression was modulated via siRNA knockdown and overexpression plasmids. Cell viability, apoptosis, and colony formation were assessed by CCK-8, flow cytometry, and clonogenic assays. The interaction between circQKI and miR-188-3p was verified by dual-luciferase reporter, RIP, and RNA pull-down. Autophagy activation was analyzed via Western blot and TEM. Subcutaneous xenograft models evaluated in vivo drug resistance. M6A modification was investigated through m6A RIP-PCR, METTL3/IGF2BP2 knockdown, and stability assays.

RESULTS: CircQKI was significantly upregulated in resistant cells and promoted DTX resistance by sponging miR-188-3p, thereby enhancing Beclin-1 expression and autophagy activation. Inhibiting Beclin-1 or co-treatment with chloroquine (CQ) partially restored DTX sensitivity. Mechanistically, METTL3-mediated m6A modification stabilized circQKI via IGF2BP2 recognition, leading to its accumulation in resistant cells. In vivo studies confirmed that circQKI overexpression reduced tumor sensitivity to DTX by enhancing autophagy.

CONCLUSION: circQKI drives DTX resistance via the miR-188-3p/Beclin-1 axis and autophagy activation, with its expression regulated by METTL3-dependent m6A modification and IGF2BP2. Targeting circQKI or autophagy pathways may offer novel therapeutic strategies to overcome DTX resistance in prostate cancer.