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Background <p>ONECUT2 is a lineage plasticity driver and therapeutic target in aggressive prostate cancer (PCa). This study investigated whether ONECUT2 gene-body DNA methylation regulates its expression and assessed its potential as a biomarker in clinical specimens.</p> Methods <p>We analyzed associations between ONECUT2 gene-body methylation, expression, and patient survival across multiple datasets. The effect of DNA methylation on ONECUT2 expression was tested in prostate cancer cell lines using a DNA methyltransferase inhibitor (DNMTi). Validation was further performed in needle biopsy samples by targeted bisulfite sequencing for DNA methylation and RT-PCR for gene expression.</p> Results <p>ONECUT2 expression strongly correlated with gene-body DNA methylation and patient survival in multiple datasets. DNMTi treatment confirmed this relationship in prostate cancer cells. In 208 biopsies from prostate cancer patients, hypermethylation of gene-body of ONECUT2 was linked to higher ONECUT2 expression and effectively distinguished tumor from adjacent normal tissue (<i>p</i> &lt; 0.001 and AUC = 0.86). It also predicted aggressive features, including higher Gleason score (<i>p</i> = 0.01 and AUC = 0.68), advanced T stage (<i>p</i> = 0.04 and AUC = 0.65), seminal vesicle invasion (<i>p</i> = 0.0024 and AUC = 0.76), and lymph node involvement (<i>p</i> = 0.0005 and AUC = 0.80).</p> Conclusion <p>Assessing ONECUT2 gene-body methylation in biopsies may serve as a surrogate for ONECUT2 expression and provide predictive insights into disease progression before surgery. Furthermore, suppressing ONECUT2 through DNMTi treatment represents a potential therapeutic strategy for aggressive PCa.</p>

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Gene-body DNA methylation of ONECUT2 predicts its expression and prostate cancer aggressiveness in needle biopsies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Yohei Sekino,
  • Hong-Tao Li,
  • Masatomo Kaneko,
  • Yuta Inoue,
  • Lorenzo Storino Ramacciotti,
  • Rongying Lu,
  • Zhenzhong Deng,
  • Xinyi Zhou,
  • Michelle Mingxue Song,
  • Aditya Desai,
  • Mingda Jin,
  • Wei Guo,
  • Xiaojing Yang,
  • Jeffrey Bhasin,
  • Nobuyuki Hinata,
  • Michael R. Freeman,
  • Inderbir Gill,
  • Manju Aron,
  • Steven Yong Cen,
  • Andre Luis Abreu,
  • Gangning Liang

摘要

Background

ONECUT2 is a lineage plasticity driver and therapeutic target in aggressive prostate cancer (PCa). This study investigated whether ONECUT2 gene-body DNA methylation regulates its expression and assessed its potential as a biomarker in clinical specimens.

Methods

We analyzed associations between ONECUT2 gene-body methylation, expression, and patient survival across multiple datasets. The effect of DNA methylation on ONECUT2 expression was tested in prostate cancer cell lines using a DNA methyltransferase inhibitor (DNMTi). Validation was further performed in needle biopsy samples by targeted bisulfite sequencing for DNA methylation and RT-PCR for gene expression.

Results

ONECUT2 expression strongly correlated with gene-body DNA methylation and patient survival in multiple datasets. DNMTi treatment confirmed this relationship in prostate cancer cells. In 208 biopsies from prostate cancer patients, hypermethylation of gene-body of ONECUT2 was linked to higher ONECUT2 expression and effectively distinguished tumor from adjacent normal tissue (p < 0.001 and AUC = 0.86). It also predicted aggressive features, including higher Gleason score (p = 0.01 and AUC = 0.68), advanced T stage (p = 0.04 and AUC = 0.65), seminal vesicle invasion (p = 0.0024 and AUC = 0.76), and lymph node involvement (p = 0.0005 and AUC = 0.80).

Conclusion

Assessing ONECUT2 gene-body methylation in biopsies may serve as a surrogate for ONECUT2 expression and provide predictive insights into disease progression before surgery. Furthermore, suppressing ONECUT2 through DNMTi treatment represents a potential therapeutic strategy for aggressive PCa.