DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase

• Published in: Nature communications Vol. 11; no. 1; pp. 1251 - 15
• Main Authors: Cao, Ji, Chen, Xiaobing, Jiang, Li, Lu, Bin, Yuan, Meng, Zhu, Difeng, Zhu, Hong, He, Qiaojun, Yang, Bo, Ying, Meidan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.03.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenosylhomocysteinase - metabolism; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; Biosynthesis; Cancer; Cell death; Cell Line, Tumor; Cystine; Depletion; Disruption; Female; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - physiology; Fibroblasts; Glutathione; Glutathione - biosynthesis; HEK293 Cells; Homocysteine; Homocysteine - metabolism; Humans; Hydrolase; Intracellular Signaling Peptides and Proteins - metabolism; Lipids; Metabolites; Mice; Mice, Knockout; Molecular modelling; Neoplasms - drug therapy; Neoplasms - pathology; Oxidative stress; PARK7 protein; Piperazines - pharmacology; Primary Cell Culture; Protein Deglycase DJ-1 - genetics; Protein Deglycase DJ-1 - metabolism; Protein Multimerization; Reactive oxygen species; RNA, Small Interfering - metabolism; Sensitivity enhancement; Therapeutic applications; Therapy; Tumor cells; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15109-y

Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.