2. Academic Validation
  3. YAP1 suppression by ZDHHC7 is associated with ferroptosis resistance and poor prognosis in ovarian clear cell carcinoma

YAP1 suppression by ZDHHC7 is associated with ferroptosis resistance and poor prognosis in ovarian clear cell carcinoma

  • Mol Cancer Ther. 2024 Jul 3. doi: 10.1158/1535-7163.MCT-24-0145.
Yoko Furutake 1,  Ken Yamaguchi 1,  Koji Yamanoi 2,  Sachiko Kitamura 1,  Shiro Takamatsu 3,  Mana Taki 4,  Masayo Ukita 5,  Yuko Hosoe 6,  Ryusuke Murakami 6,  Kaoru Abiko 7,  Akihito Horie 2,  Junzo Hamanishi 8,  Tsukasa Baba 9,  Noriomi Matsumura 10,  Masaki Mandai 8
Affiliations

Affiliations

  • 1 Kyoto University, Kyoto, Japan.
  • 2 Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
  • 3 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 4 Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 5 Shizuoka General Hospital, Kyoto, Japan.
  • 6 Kyoto University, Kyoto, Kyoto, Japan.
  • 7 National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  • 8 Kyoto University Gradute School of Medicine, Kyoto, Kyoto, Japan.
  • 9 Iwate Medical University, Shiwa, Japan.
  • 10 Kindai University, Osakasayama, Osaka, Japan.
PMID: 38958503 DOI: 10.1158/1535-7163.MCT-24-0145
Abstract

Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment due to excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming Ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of Ferroptosis resistance. This study aimed to determine whether OCCC is resistant to Ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the Ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear Yes-associated protein 1(YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced Ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced Ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced Ferroptosis in OCCC. Thus, overcoming Ferroptosis resistance is a potential therapeutic strategy for OCCC.

Figures
Products