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Background <p>Histone lactylation has emerged as an epigenetic driver of tumor chemoresistance. Our prior work identified the phytochemical combination icariin-curcumol (Ica-Cur) as a potential therapeutic agent against docetaxel (DTX)-resistant prostate cancer (PCa). This study aimed to investigate the mechanistic link between histone lactylation and DTX resistance in PCa, and evaluates Ica-Cur’s regulatory role in this process.</p> Methods <p>DTX-resistant LNCaP/R cells were generated from parental LNCaP PCa cells. Xenograft models were established in BALB/c nude mice using both cell lines. Interventions included pharmacological modulation of glycolysis (sodium lactate [Nala], a glycolysis activator and 2-deoxy-D-glucose [2-DG], a glycolysis inhibitor) and genetic silencing of forkhead box M1 (FOXM1) via lentiviral constructs (sh-FOXM1). The enrichment of histone H3K18 lactylation (H3K18la) at the <i>FOXM1</i> promoter was validated. Tumor growth, lactate levels, lactate dehydrogenase (LDH) activity, proliferation, and apoptosis were systematically analyzed.</p> Results <p>Resistant LNCaP/R models exhibited significant upregulation of H3K18la and FOXM1 compared to controls. Nala increased lactate production, enhanced H3K18la deposition, and stimulated proliferation while suppressing apoptosis. Conversely, 2-DG reduced H3K18la deposition and inhibited proliferation. FOXM1 expression was directly regulated by H3K18la, with sh-FOXM1 reducing LDH activity, inhibiting proliferation, and inducing apoptosis. Ica-Cur restored DTX sensitivity by suppressing H3K18la and FOXM1 expression.</p> Conclusion <p>These findings identify H3K18la-mediated FOXM1 activation as a novel mechanism underlying DTX resistance in PCa. Ica-Cur may represent a promising therapeutic agent by targeting lactylation-dependent epigenetic regulation and FOXM1-driven transcriptional activity, supporting its clinical potential for overcoming chemoresistance.</p>

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Icariin-curcumol inhibits histone H3K18 lactylation and FOXM1 expression to enhance the sensitivity of prostate cancer cells to docetaxel

  • 期刊论文

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  • 发表日期：

    2025年11月25日

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  • Wen Sheng,
  • Yingqiu Li,
  • Tao Tan,
  • Xincheng Yu,
  • Xuxi Huang,
  • Lingyi Li,
  • Canying Zhang,
  • Yalin Chen,
  • Lumei Liu,
  • Min Feng,
  • Haitao Dang,
  • Qinghu He,
  • Wenjing Xu

摘要

Background

Histone lactylation has emerged as an epigenetic driver of tumor chemoresistance. Our prior work identified the phytochemical combination icariin-curcumol (Ica-Cur) as a potential therapeutic agent against docetaxel (DTX)-resistant prostate cancer (PCa). This study aimed to investigate the mechanistic link between histone lactylation and DTX resistance in PCa, and evaluates Ica-Cur’s regulatory role in this process.

Methods

DTX-resistant LNCaP/R cells were generated from parental LNCaP PCa cells. Xenograft models were established in BALB/c nude mice using both cell lines. Interventions included pharmacological modulation of glycolysis (sodium lactate [Nala], a glycolysis activator and 2-deoxy-D-glucose [2-DG], a glycolysis inhibitor) and genetic silencing of forkhead box M1 (FOXM1) via lentiviral constructs (sh-FOXM1). The enrichment of histone H3K18 lactylation (H3K18la) at the FOXM1 promoter was validated. Tumor growth, lactate levels, lactate dehydrogenase (LDH) activity, proliferation, and apoptosis were systematically analyzed.

Results

Resistant LNCaP/R models exhibited significant upregulation of H3K18la and FOXM1 compared to controls. Nala increased lactate production, enhanced H3K18la deposition, and stimulated proliferation while suppressing apoptosis. Conversely, 2-DG reduced H3K18la deposition and inhibited proliferation. FOXM1 expression was directly regulated by H3K18la, with sh-FOXM1 reducing LDH activity, inhibiting proliferation, and inducing apoptosis. Ica-Cur restored DTX sensitivity by suppressing H3K18la and FOXM1 expression.

Conclusion

These findings identify H3K18la-mediated FOXM1 activation as a novel mechanism underlying DTX resistance in PCa. Ica-Cur may represent a promising therapeutic agent by targeting lactylation-dependent epigenetic regulation and FOXM1-driven transcriptional activity, supporting its clinical potential for overcoming chemoresistance.