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Updated: Sep 17, 2025

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Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer

Shouhai Zhu1, Huanyao Gao2, Dan Jiang2

  • 1Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Molecular Cell
|June 27, 2025
PubMed

Insights

Short isoform of nuclear-receptor-binding SET domain protein 3 (NSD3S) drives resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) in prostate cancer. Targeting NSD3S with PROTACs restores PARPi sensitivity, offering a new therapeutic strategy for mCRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 alterations.
  • Therapy resistance to PARPi remains a significant clinical challenge, limiting treatment effectiveness.

Purpose of the Study:

  • To investigate the mechanisms underlying PARPi resistance in mCRPC.
  • To identify novel therapeutic targets for overcoming PARPi resistance.

Main Methods:

  • Investigated the role of cullin 3 (CUL3)ZBTB2 E3 ligase complex in regulating NSD3.
  • Utilized cell-line-derived xenograft and patient-derived xenograft (PDX) mouse models.
  • Employed NSD3-targeting proteolysis-targeting chimera (PROTAC) to degrade NSD3S.

Main Results:

  • Dysregulated ubiquitination by CUL3ZBTB2 upregulates NSD3S, conferring PARPi resistance.
  • NSD3S localizes at stalled replication forks, antagonizing MRE11 recruitment and stabilizing DNA.
  • Pharmacological degradation of NSD3S using PROTACs enhances PARPi sensitivity in preclinical models.

Conclusions:

  • NSD3S is a key driver of PARPi resistance in mCRPC.
  • Targeting NSD3S degradation represents a promising strategy to improve PARPi efficacy in prostate cancer.
Keywords:
CUL3MRE11NSD3PARP inhibitorPTIPprostate cancerproteolysis-targeting chimerareplication fork

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