circLPAR3 drives chemotherapy resistance in prostate cancer

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 N6-methyladenosine (m6A) 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

Funding Information:

The Scientific Research Project of Jiangsu Provincial Health and Wellness Commission (China) (No. ZD2021028)
Jiangsu Provincial Postgraduate Research Innovation Program (China) (No. KYCX23_1926)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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Fichiers joints

(A) Venn plot of the differentially expressed docetaxel-resistant circRNAs. (B) The expression of circLPAR3 was detected by quantitative reverse transcription PCR in docetaxel-resistant prostate cancer cells (22Rv1-DR, DU145-DR, and PC3-DR) and sensitive cell lines (22Rv1, DU145, and PC3). (C) Schematic illustration of circLPAR3 formation via the circularization from exon 2 in the LPAR3 gene. (D) The expression of circLPAR3 in cDNA and gDNA of 22Rv1 and DU145 cells were confirmed by quantitative reverse transcription PCR with the divergent and convergent primers. (E) The relative expression of circLPAR3 and LPAR3 was measured by quantitative reverse transcription PCR after treatment with RNase R. (F) Cells were treated with actinomycin D (2 μg/mL) and harvested after 0, 4, 8, 12 and 24 h. Relative expression of circLPAR3 and LPAR3 was calculated and normalized to 0 h to compare the RNA stability. (G) Nuclear–cytoplasmic fractionation assay was used to assess the intracellular location of circLPAR3 in drug-resistant and parent cells. U6 was considered as a nuclear control and β-actin was used as a cytoplasmic protein control. (H) The subcellular location of circLPAR3 was also evaluated by fluorescence in situ hybridization assays. Nuclei were stained with DAPI. ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001; ns, nonsignificant.
(A) Representative images of xenograft tumors in the oe-circLPAR3 22Rv1-DR group and its control group (vector) after treatment with docetaxel or DMSO. (B, C) Tumor growth curves were plotted and tumor weights were measured. (D) Immunohistochemistry assessment of Ki-67 and CHAC1 expression in the oe-circLPAR3 group and its control group. (E) METTL3/IGF2BP2-regulated circLPAR3 promotes proliferation of drug-resistant cells and confers ferroptosis resistance to docetaxel-resistant prostate cancer cells by binding to PCBP2 and inhibiting the latter’s stabilizing effect on CHAC1 mRNA. ∗∗P < 0.01 and ∗∗∗∗P < 0.0001.
(A) Silver staining assay and Western blotting assay were conducted to verify the binding of circLPAR3 to PCBP2. (B) PCBP2-RNA immunoprecipitation assay was conducted to verify the binding of PCBP2 to circLPAR3. (C) Fluorescence in situ hybridization and immunofluorescence assays were carried out to indicate the co-localization of circLPAR3 and PCBP2. (D) PCBP2-RNA immunoprecipitation assay was conducted to verify the binding of PCBP2 to CHAC1. (E) Binding of PCBP2 on CHAC1 mRNA was predicted using RBPsuite Predicted. ∗∗∗P < 0.001 and ∗∗∗∗P < 0.0001.

29/09/2026 Compuscript Ltd

Regions: Europe, Ireland, Asia, China

Keywords: Science, Life Sciences

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