2. Academic Validation
  3. KAT6A Condensates Impair PARP1 Trapping of PARP Inhibitors in Ovarian Cancer

KAT6A Condensates Impair PARP1 Trapping of PARP Inhibitors in Ovarian Cancer

  • Adv Sci (Weinh). 2024 Jul 8:e2400140. doi: 10.1002/advs.202400140.
Zhiyan Zhan 1 2,  Jiarong Zhang 3,  Huisheng Liang 4,  Chong Wang 5,  Li Hong 1 2,  Wenxue Liu 3
Affiliations

Affiliations

  • 1 Department of Clinical Nutrition, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Clinical Research Center, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 3 Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 4 Department of Gynecology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, 361000, China.
  • 5 Department of Obstetrics and Gynecology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080, China.
PMID: 38973255 DOI: 10.1002/advs.202400140
Abstract

Most clinical PARP inhibitors (PARPis) trap PARP1 in a chromatin-bound state, leading to PARPi-mediated cytotoxicity. PARPi resistance impedes the treatment of ovarian Cancer in clinical practice. However, the mechanism by which Cancer cells overcome PARP1 trapping to develop PARPi resistance remains unclear. Here, it is shown that high levels of KAT6A promote PARPi resistance in ovarian Cancer, regardless of its catalytic activity. Mechanistically, the liquid-liquid phase separation (LLPS) of KAT6A, facilitated by APEX1, inhibits the cytotoxic effects of PARP1 trapping during PARPi treatment. The stable KAT6A-PARP1-APEX1 complex reduces the amount of PARP1 trapped at the DNA break sites. In addition, inhibition of KAT6A LLPS, rather than its catalytic activity, impairs DNA damage repair and restores PARPi sensitivity in ovarian Cancer both in vivo and in vitro. In conclusion, the findings demonstrate the role of KAT6A LLPS in fostering PARPi resistance and suggest that repressing KAT6A LLPS can be a potential therapeutic strategy for PARPi-resistant ovarian Cancer.

Keywords

APEX1; KAT6A; PARP1 trapping; liquid‐liquid phase separation; ovarian cancer.

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