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Background <p>Poly(ADP-ribose) polymerase (PARP) inhibitor resistance represents a major clinical challenge in both homologous recombination deficiency-positive (HRD<sup>+</sup>) and deficiency-negative (HRD<sup>−</sup>) high-grade serous ovarian carcinoma (HGSOC). <i>ACSF2</i> is aberrantly overexpressed in various malignancies and associated with poor patient prognosis. However, its role and underlying mechanism in PARP inhibitor resistance remain unclear.</p> Objective <p>This study aimed to investigate whether <i>ACSF2</i> modulates PARP inhibitor resistance by regulating p53-binding protein 1 (53BP1) nuclear foci formation and to determine if <i>ACSF2</i> influences histone H4 Lysine 20 di-methylation (H4K20me2)-mediated 53BP1 recruitment <i>via KMT5B</i> in HRD<sup>−</sup> HGSOC.</p> Methods <p>Using machine learning, <i>ACSF2</i> was identified as a key resistance gene to PARP inhibitor. This discovery was based on an integrated analysis of six platinum-sensitive recurrent ovarian cancer (OC) cell lines (HRD<sup>±</sup>), four PARP inhibitor-resistant patient-derived organoid (PDO) models, and 181&#xa0;°C tissue samples. Isogenic resistant cell lines were established to validate the role of <i>ACSF2</i>. The functional impact of <i>ACSF2</i> perturbation was assessed by evaluating 53BP1, breast cancer type 1 susceptibility protein (BRCA1), and phosphorylated H2A histone family member x (γH2AX) foci formation, along with epigenetic markers (<i>KMT5B</i> and H4K20me2). The therapeutic potential of targeting <i>ACSF2</i> was further examined through in vitro, in vivo, and PDO models.</p> Results <p><i>ACSF2</i> was provisionally identified as key mediator of PARP inhibitor resistance, with high expression correlating with poorer median overall survival in patients (42.00 vs. 49.60 months, <i>P</i> &lt; 0.05). Similarly, <i>ACSF2</i> acted as a key regulator of Niraparib sensitivity. Overexpression of <i>ACSF2</i> increased the IC<sub>50</sub> (72&#xa0;h) from 146.89 ± 9.08 <i>µ</i>mol/L to 192.27 ± 4.24 <i>µ</i>mol/L (<i>P</i> &lt; 0.001), while its knockdown reduced the IC<sub>50</sub> to 92.81 ± 2.62 <i>µ</i>mol/L (<i>P</i> &lt; 0.001). Mechanistically, <i>ACSF2</i> suppression significantly enhanced 53BP1 nuclear foci formation (positive cells increased from 12.00 ± 2.90% to 76.65 ± 7.23%; foci count increased &gt; 12-fold; <i>P</i> &lt; 0.001) and suppressed Niraparib-induced BRCA1 foci (median foci reduced from 38.00 [23.24–52.76] to 3.86 [1.50–6.21]), concomitantly promoting DNA damage. This process was associated with upregulation of H4K20me2, which is regulated by KMT5B.</p> Conclusion <p><i>ACSF2</i> promotes Niraparib resistance in HRD<sup>−</sup> HGSOC by modulating the <i>KMT5B</i>-H4K20me2 axis, thereby inhibiting 53BP1 nuclear aggregation. Targeting <i>ACSF2</i> restores 53BP1-mediated DNA damage response and re-sensitizes tumors to PARP inhibitor.</p>

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ACSF2 Functions as a regulatory switch for PARP inhibitor sensitivity in platinum-sensitive and homologous recombination–proficient high-grade serous ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Sijia Cheng,
  • Jiayi Li,
  • Yunzhi Ling,
  • Jiaru Luo,
  • Dan Zhou,
  • Tianle Mao,
  • Tingting Luo,
  • Yanyang Tu,
  • Jinlin Du,
  • Minghui Zhou,
  • Qingsong Qin,
  • Yanqin Ji

摘要

Background

Poly(ADP-ribose) polymerase (PARP) inhibitor resistance represents a major clinical challenge in both homologous recombination deficiency-positive (HRD+) and deficiency-negative (HRD−) high-grade serous ovarian carcinoma (HGSOC). ACSF2 is aberrantly overexpressed in various malignancies and associated with poor patient prognosis. However, its role and underlying mechanism in PARP inhibitor resistance remain unclear.

Objective

This study aimed to investigate whether ACSF2 modulates PARP inhibitor resistance by regulating p53-binding protein 1 (53BP1) nuclear foci formation and to determine if ACSF2 influences histone H4 Lysine 20 di-methylation (H4K20me2)-mediated 53BP1 recruitment via KMT5B in HRD− HGSOC.

Methods

Using machine learning, ACSF2 was identified as a key resistance gene to PARP inhibitor. This discovery was based on an integrated analysis of six platinum-sensitive recurrent ovarian cancer (OC) cell lines (HRD±), four PARP inhibitor-resistant patient-derived organoid (PDO) models, and 181 °C tissue samples. Isogenic resistant cell lines were established to validate the role of ACSF2. The functional impact of ACSF2 perturbation was assessed by evaluating 53BP1, breast cancer type 1 susceptibility protein (BRCA1), and phosphorylated H2A histone family member x (γH2AX) foci formation, along with epigenetic markers (KMT5B and H4K20me2). The therapeutic potential of targeting ACSF2 was further examined through in vitro, in vivo, and PDO models.

Results

ACSF2 was provisionally identified as key mediator of PARP inhibitor resistance, with high expression correlating with poorer median overall survival in patients (42.00 vs. 49.60 months, P < 0.05). Similarly, ACSF2 acted as a key regulator of Niraparib sensitivity. Overexpression of ACSF2 increased the IC50 (72 h) from 146.89 ± 9.08 µmol/L to 192.27 ± 4.24 µmol/L (P < 0.001), while its knockdown reduced the IC50 to 92.81 ± 2.62 µmol/L (P < 0.001). Mechanistically, ACSF2 suppression significantly enhanced 53BP1 nuclear foci formation (positive cells increased from 12.00 ± 2.90% to 76.65 ± 7.23%; foci count increased > 12-fold; P < 0.001) and suppressed Niraparib-induced BRCA1 foci (median foci reduced from 38.00 [23.24–52.76] to 3.86 [1.50–6.21]), concomitantly promoting DNA damage. This process was associated with upregulation of H4K20me2, which is regulated by KMT5B.

Conclusion

ACSF2 promotes Niraparib resistance in HRD− HGSOC by modulating the KMT5B-H4K20me2 axis, thereby inhibiting 53BP1 nuclear aggregation. Targeting ACSF2 restores 53BP1-mediated DNA damage response and re-sensitizes tumors to PARP inhibitor.