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Updated: Feb 16, 2026

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p300-mediated acetylation of KCNN4 drives enzalutamide resistance in prostate cancer

Weiqiang Song1, Jiankun Zhang1, Zekun Xin1

  • 1Department of Urology, Hebei Petrochina Central Hospital, Xinkai Road NO.51, Langfang City, Hebei Province, 065000, China.

Experimental Cell Research
|February 14, 2026
PubMed

Insights

Targeting the p300-KCNN4 pathway can overcome enzalutamide resistance in prostate cancer. Inhibiting p300 stabilizes KCNN4, resensitizing resistant cells to treatment and suppressing tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Enzalutamide resistance is a major challenge in castration-resistant prostate cancer (CRPC).
  • Potassium calcium-activated channel subfamily N member 4 (KCNN4) is implicated in therapeutic failure.
  • Understanding resistance mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of KCNN4 in enzalutamide resistance.
  • To elucidate the regulatory mechanism of KCNN4 stability.
  • To explore therapeutic strategies targeting the p300-KCNN4 axis.

Main Methods:

  • Analysis of KCNN4 expression in enzalutamide-resistant prostate cancer (PCa) cells and clinical tissues.
  • Investigation of the interaction between p300 and KCNN4 using biochemical assays.
  • Assessment of the effects of p300 inhibition on KCNN4 acetylation, degradation, and enzalutamide sensitivity in vitro and in vivo.
  • Evaluation of KCNN4 knockdown in combination with enzalutamide in xenograft models.

Main Results:

  • KCNN4 is upregulated in resistant PCa, correlating with poor prognosis.
  • p300 acetylates KCNN4 at lysine 16, inhibiting its ubiquitination and degradation, thus stabilizing the protein.
  • p300 inhibition reduces KCNN4 acetylation, promotes its degradation, and resensitizes resistant cells to enzalutamide.
  • KCNN4 knockdown suppresses tumor growth and synergizes with enzalutamide.

Conclusions:

  • A novel epigenetic mechanism links p300-mediated acetylation to KCNN4 stability.
  • Targeting the p300-KCNN4 axis offers a promising strategy to overcome enzalutamide resistance in advanced prostate cancer.
  • This approach could improve therapeutic outcomes for CRPC patients.
Keywords:
AcetylationChemoresistanceKCNN4Prostate cancerUbiquitination

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