Hsa_circ_0038737 promotes PARPi resistance in castration-resistant prostate cancer via IGF2BP3-mediated DNPH1 mRNA stabilization

  • Mol Cancer. 2025 Oct 2;24(1):238. doi: 10.1186/s12943-025-02447-y.
Zhongyuan Wang  #  1  2  3 ,  Qintao Ge  #  1  2  3 ,  Aihetaimujiang Anwaier  #  1  2  3 ,  Shiwei Liu  #  1  2  3 ,  Xi Tian  1  2  3 ,  Zihao Zhang  1  2  3 ,  Tao Feng  1  2  3 ,  Zhe Hong  1  2  3 ,  Dingwei Ye  4  5  6 ,  Wenhao Xu  7  8  9 ,  Xiaojian Qin  10  11  12
Affiliations
  • 1. Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P.R. China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, P. R. China.
  • 3. Shanghai Genitourinary Cancer Institute, Shanghai, 200032, P.R. China.
  • 4. Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P.R. China. [email protected].
  • 5. Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, P. R. China. [email protected].
  • 6. Shanghai Genitourinary Cancer Institute, Shanghai, 200032, P.R. China. [email protected].
  • 7. Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P.R. China. [email protected].
  • 8. Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, P. R. China. [email protected].
  • 9. Shanghai Genitourinary Cancer Institute, Shanghai, 200032, P.R. China. [email protected].
  • 10. Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P.R. China. [email protected].
  • 11. Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, P. R. China. [email protected].
  • 12. Shanghai Genitourinary Cancer Institute, Shanghai, 200032, P.R. China. [email protected].
  • # Contributed equally.
PMID: 41039575 DOI: 10.1186/s12943-025-02447-y
Abstract

Background: Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a major challenge to therapeutic efficacy in castration-resistant prostate Cancer (CRPC). Although circular RNAs (circRNAs) have emerged as critical regulators in Cancer biology, their involvement in PARPi resistance remains largely uncharacterized.

Objective: This study aims to elucidate the molecular mechanism by which hsa_circ_0038737 modulates PARPi resistance in CRPC through post-transcriptional regulatory pathways.

Methods: We employed a comprehensive set of in vitro and in vivo approaches, including qRT-PCR, RNA Sequencing, RNA-protein pull-down, RNA immunoprecipitation, functional assays, and xenograft/Organoid models, to investigate the biological function and mechanistic role of hsa_circ_0038737 in CRPC progression and therapeutic response.

Results: We identified hsa_circ_0038737 as a nuclear-enriched circRNA significantly upregulated in CRPC, with expression levels correlating with poor prognosis and aggressive clinical features. Mechanistically, hsa_circ_0038737 interacts with RNA-binding protein (RBP) IGF2BP3, enhancing the stability of DNPH1 mRNA, a nucleotide sanitizer critical for DNA repair. The circRNA-RBP-mRNA regulatory axis promotes PARPi resistance by facilitating DNA damage repair capacity. Moreover, we revealed that reverse-complementary Alu elements mediate circRNA biogenesis, with HNRNPDL facilitating this process. Pharmacologic inhibition of DNPH1 effectively restored PARPi sensitivity both in vitro and in vivo.

Conclusion: Our findings reveal a novel hsa_circ_0038737/IGF2BP3/DNPH1 axis driving PARPi resistance in CRPC, offering promising potential biomarkers and therapeutic targets to overcome resistance and improve treatment outcomes in advanced prostate Cancer.

Keywords
Castration-resistant prostate cancer (CRPC); Circular RNA (circRNA); DNPH1 stabilization; IGF2BP3; PARP inhibitor.
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