Cytoglobin attenuates melanoma malignancy but protects melanoma cells from ferroptosis

Zou,Zuquan; Yu,Qingyao; Yang,Yong; Wang,Feng; Zhu,Pan; Zhang,Xiaohong; Zhang,Jinjie

doi:10.3892/mmr.2024.13343

Cytoglobin attenuates melanoma malignancy but protects melanoma cells from ferroptosis

Authors:
- Zuquan Zou
- Qingyao Yu
- Yong Yang
- Feng Wang
- Pan Zhu
- Xiaohong Zhang
- Jinjie Zhang
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Affiliations: Department of Health, Beilun District Center for Disease Control and Prevention, Ningbo, Zhejiang 315899, P.R. China, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315832, P.R. China, Department of Clinical Laboratory of The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315020, P.R. China, Department of Laboratory Medicine, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China, Zhejiang Key Laboratory of Pathophysiology, Medical School, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
Published online on: September 26, 2024 https://doi.org/10.3892/mmr.2024.13343
Article Number: 219
Copyright: © Zou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cutaneous malignant melanoma is the most aggressive and the deadliest form of skin cancer. There are two types of limitations which universally exist in current melanoma therapy: Adverse effects and reduced efficiency. Cytoglobin (CYGB), an iron hexacoordinated globin, is highly enriched in melanocytes and frequently epigenetically silenced during melanoma genesis. The present study aimed to explore its potential role as a biomarker for ferroptosis treatment. It was observed that B16F10 and A375 melanoma cells with loss of CYGB expression were highly sensitive to ferroptosis inducers RSL3 and erastin, whereas G361 melanoma cells with highly enriched CYGB were resistant to RSL3 or erastin. Ectopically overexpressed CYGB rendered B16F10 and A375 cells resistant to RSL3 or erastin, accompanied by decreased proliferation and epithelial‑mesenchymal transition (EMT). By contrast, knockdown of CYGB expression made G361 cells sensitive to ferroptosis induction but induced proliferation and EMT progression of G361 cells. Mechanistically, CYGB‑induced resistance of melanoma cells to ferroptosis may have been associated, in part, with i) Suppression of EMT; ii) upregulation of glutathione peroxidase 4 expression; iii) decrease of labile iron pool. In vivo study also demonstrated that CYGB overexpression rendered xenograft melanoma much more resist to RSL3 treatment. Based on these findings, CYGB is a potential therapeutic biomarker to screen the melanoma patients who are most likely benefit from ferroptosis treatment.

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