YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma

Jul 3, 2024Molecular cancer therapeutics

Lower YAP1 Levels Linked to Resistance to Ferroptosis and Worse Outcomes in Ovarian Clear Cell Cancer Due to ZDHHC7

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Alzheimers & Treatments on OpenScience ↗PubMed ↗DOI ↗

Abstract

Ovarian clear cell carcinoma (OCCC) cells exhibit resistance to the ferroptosis inducer erastin.

OCCC arises from benign endometriotic cysts and is characterized by poor prognosis, especially in advanced stages.
Unlike ovarian high-grade serous carcinoma cells, OCCC cells remain unaffected by lipid peroxidation despite exposure to oxidative stress.
The Hippo signaling pathway was found to be enriched in OCCC cell lines and clinical samples.
Patients with low expression of nuclear yes-associated protein 1 (YAP1) showed significantly poorer prognosis in OCCC.
Activation of YAP1 enhanced ferroptosis in OCCC cell lines.
Suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) increased ferroptosis through YAP1 activation in OCCC cell lines.

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Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of 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.

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YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma

Abstract

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