Docetaxel (DTX) remains the standard first-line chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). Although many patients initially respond to treatment, resistance inevitably develops, limiting long-term therapeutic benefit and contributing to disease progression. Increasing evidence suggests that dysregulated non-coding RNAs and ferroptosis pathways influence chemoresistance, yet the molecular mechanisms connecting these processes remain poorly understood. Identifying regulators of DTX resistance may therefore provide new opportunities to improve treatment outcomes for patients with advanced prostate cancer.
In a recent study published in Genes & Diseases , researchers from Nanjing Medical University identified circLPAR3 as a key mediator of docetaxel resistance in prostate cancer. Using RNA sequencing, functional assays, transcriptomic analyses, and mouse xenograft models, the investigators demonstrated that circLPAR3 promotes tumor growth under chemotherapy by suppressing ferroptosis.
Initially, the investigators identified circLPAR3 (hsa_circ_0004390), derived from the back-splicing of exons 2 and 3 of the LPAR3 gene. While expression of the parental LPAR3 gene did not differ significantly between parental and resistant cell lines, circLPAR3 was highly upregulated in resistant variants. Quantitative PCR and fluorescence in situ hybridization (FISH) successfully localized circLPAR3 to the cellular cytoplasm. Further experiments showed that circLPAR3 is actively regulated by METTL3-mediated N 6-methyladenosine ( m 6A) methylation. This specific modification promotes the recruitment of the reader protein IGF2BP2, which directly binds and stabilizes circLPAR3, thereby enhancing transcript stability and driving prostate cancer chemoresistance.
Mechanistically, biochemical assays demonstrated that cytoplasmic circLPAR3 physically interacts with Poly(RC) Binding Protein 2 (PCBP2). PCBP2 typically binds to and stabilizes the messenger RNA of CHAC1 (ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1), an essential driver of the ferroptotic cascade. The direct binding of circLPAR3 to PCBP2 suppresses PCBP2-mediated stabilization, leading to the rapid degradation of CHAC1 mRNA.
Consequently, circLPAR3-mediated depletion of CHAC1 inhibits DTX-induced ferroptosis, characterized by reduced intracellular divalent iron accumulation, decreased lipid peroxidation, and lowered malondialdehyde levels, alongside cellular glutathione preservation. Conversely, silencing circLPAR3 or overexpressing CHAC1 successfully restored sensitivity to DTX by promoting ferroptosis. The physiological significance of this pathway was validated in vivo using subcutaneous xenograft mouse models. Overexpression of circLPAR3 accelerated tumor growth under DTX treatment, accompanied by decreased intratumoral CHAC1 expression.
Overall, this study identifies circLPAR3 as a previously unrecognized regulator of docetaxel resistance in prostate cancer by linking epitranscriptomic regulation with ferroptosis suppression. These findings highlight circLPAR3 as a promising biomarker for treatment response and suggest that targeting this regulatory network could represent a novel strategy for overcoming chemotherapy resistance in advanced prostate cancer.
Reference
Title of Original Paper : N6-methyladenosine-modified circLPAR3 drives docetaxel resistance in prostate cancer by suppressing ferroptosis through the PCBP2/CHAC1 axis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101816
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