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  6. 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

Yoko Furutake1, Ken Yamaguchi1, Koji Yamanoi1

  • 1Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan.

Molecular Cancer Therapeutics
|July 3, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Ovarian clear cell carcinoma (OCCC) cells resist ferroptosis, a cell death pathway. Targeting YAP1 activation, regulated by ZDHHC7, may overcome this resistance and treat OCCC.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Ovarian clear cell carcinoma (OCCC) presents unique clinical features and poor prognosis, often linked to therapeutic resistance.
  • OCCC develops in an oxidative stress environment due to iron accumulation, suggesting inherent resistance mechanisms.
  • Ferroptosis, an iron-dependent cell death, is a potential therapeutic target, but its role in OCCC resistance is unclear.

Purpose of the Study:

  • To investigate OCCC's resistance to ferroptosis.
  • To elucidate the underlying molecular mechanisms of ferroptosis resistance in OCCC.
  • To explore therapeutic strategies targeting ferroptosis in OCCC.

Main Methods:

  • Comparative analysis of OCCC cells and ovarian high-grade serous carcinoma cells under oxidative stress.

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  • Cell viability assays using ferroptosis inducers like erastin.
  • Samroc analysis to assess Hippo signaling pathway enrichment.
  • Investigation of the role of Yes-associated protein 1 (YAP1) and ZDHHC7 in ferroptosis.
  • Mouse xenograft models to evaluate therapeutic efficacy.
  • Main Results:

    • OCCC cells exhibit resistance to ferroptosis-inducing agents despite oxidative stress.
    • The Hippo signaling pathway, particularly YAP1, is implicated in OCCC ferroptosis resistance.
    • Low nuclear YAP1 expression correlates with poor OCCC prognosis.
    • YAP1 activation enhances ferroptosis in OCCC cells.
    • Suppression of ZDHHC7 promotes ferroptosis via YAP1 activation.

    Conclusions:

    • OCCC cells possess intrinsic resistance to ferroptosis, mediated by the Hippo signaling pathway and YAP1.
    • ZDHHC7 plays a role in regulating ferroptosis sensitivity in OCCC through YAP1.
    • Targeting ferroptosis resistance by modulating YAP1 activation presents a promising therapeutic avenue for OCCC.