Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance

Haohao Huang, Songyang Zhang, Yuanyuan Li, Zhaodan Liu, Lanjuan Mi, Yan Cai, Xinzheng Wang, Lishu Chen, Haowen Ran, Dake Xiao, Fangye Li, Jiaqi Wu, Tingting Li, Qiuying Han, Liang Chen, Xin Pan, Huiyan Li, Tao Li, Kun He, Ailing Li, Xuemin Zhang, Tao Zhou, Qing Xia () and Jianghong Man ()
Additional contact information
Haohao Huang: National Center of Biomedical Analysis
Songyang Zhang: National Center of Biomedical Analysis
Yuanyuan Li: National Center of Biomedical Analysis
Zhaodan Liu: National Center of Biomedical Analysis
Lanjuan Mi: National Center of Biomedical Analysis
Yan Cai: National Center of Biomedical Analysis
Xinzheng Wang: National Center of Biomedical Analysis
Lishu Chen: National Center of Biomedical Analysis
Haowen Ran: National Center of Biomedical Analysis
Dake Xiao: National Center of Biomedical Analysis
Fangye Li: First Medical Center of PLA General Hospital
Jiaqi Wu: National Center of Biomedical Analysis
Tingting Li: National Center of Biomedical Analysis
Qiuying Han: National Center of Biomedical Analysis
Liang Chen: National Center of Biomedical Analysis
Xin Pan: National Center of Biomedical Analysis
Huiyan Li: National Center of Biomedical Analysis
Tao Li: National Center of Biomedical Analysis
Kun He: National Center of Biomedical Analysis
Ailing Li: National Center of Biomedical Analysis
Xuemin Zhang: National Center of Biomedical Analysis
Tao Zhou: National Center of Biomedical Analysis
Qing Xia: National Center of Biomedical Analysis
Jianghong Man: National Center of Biomedical Analysis

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Low levels of reactive oxygen species (ROS) are crucial for maintaining cancer stem cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.

Date: 2021
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DOI: 10.1038/s41467-021-24108-6

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