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Targeting the DNA methylation-H3K27me3 switch reverses castration resistance and immunosuppression via ADAMTS1-driven

Xiang Wu1,2, Xiaoyi Song2,3, Bo Li1,2

  • 1Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China.

Proceedings of the National Academy of Sciences of the United States of America
|June 18, 2026
PubMed

Insights

Dual epigenetic therapy overcomes resistance in castration-resistant prostate cancer (CRPC) by targeting DNA methylation and H3K27me3. This approach reactivates ADAMTS1, degrades the tumor stroma, and enhances anti-tumor immunity for significant tumor suppression.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Castration-resistant prostate cancer (CRPC) develops resistance to androgen deprivation therapy (ADT) through epigenetic mechanisms.
  • A compensatory epigenetic switch involving DNA methylation and H3K27me3 repression acts as a barrier to epigenetic therapies in CRPC.

Purpose of the Study:

  • To investigate the compensatory epigenetic switch between DNA methylation and H3K27me3 in CRPC.
  • To evaluate a dual-targeting therapy combining DNMT inhibitors (DNMTis) and EZH2 inhibition for CRPC treatment.

Main Methods:

  • Integrative multiomics analyses to identify epigenetic alterations.
  • In vitro and in vivo studies using CRPC models.
  • Assessment of tumor suppression, immune cell infiltration, and molecular signaling pathways.

Main Results:

  • DNMTis alone lead to EZH2-dependent H3K27me3 accumulation at the ADAMTS1 locus, promoting fibrotic niche formation and resistance.
  • Dual targeting of DNMTs and EZH2 reactivates ADAMTS1, degrades extracellular matrix (ECM) stroma, and suppresses FAK/MAPK/EMT signaling.
  • Combination therapy achieves >90% tumor suppression in immunocompetent models, enhances CD8+ T cell infiltration, and reduces immunosuppressive cells.

Conclusions:

  • Epigenetic-ECM coevolution is a key feature of CRPC resistance.
  • Dual epigenetic therapy targeting DNMTs and EZH2 effectively dismantles the therapy-resistant niche in CRPC.
  • This combination strategy offers a promising therapeutic approach for CRPC by overcoming stromal and immune resistance.
Keywords:
ADAMTS1CRPCdual epigenetic therapyepigenetic switchextracellular matrix remodeling

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