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

Abstract

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.

C Terminus of DJ-1 Determines Its Homodimerization, Deglycation Activity and Suppression of Ferroptosis

“…Besides, the suppression was more obvious in DJ-1 ΔC3 and L187E mutants than V51C mutant, indicating that the hydrophobic C terminus may have other effects such as involving regulation of signaling pathway [4, 6, 38]. All these data supported our previous discovery that DJ-1 was a negative modulator of ferroptosis providing new opportunities to facilitate ferroptosis-based cancer therapy [14].…”

“…Given that recent study has suggested that DJ-1 could suppress ferroptosis triggered by lipid ROS, the impact of DJ-1 C terminus on the suppression of ferroptosis was next investigated [14]. We utilized Erastin, a classic ferroptosis inducer, to build the model of ferroptosis.…”

“…Mechanistically, the role of DJ-1 as an abundant antioxidant scavenger of soluble ROS (such as H2O2) is related to the antioxidant transcriptional master regulator nuclear factor erythroid 2-related factor 2 (NRF2), which orchestrates the expression of genes coding for stress response and antioxidant proteins [9, 13]. In addition, we have shown that DJ-1 function as a key factor protecting tumor cells by affecting both soluble reactive oxygen species (ROS) and lipid ROS with distinct mechanisms [14, 15]. The different oxidation states of DJ-1 determines the cell fate via either activating autophagy or apoptosis through regulation of the activity of ASK1, which is based on the activity of DJ-1 against soluble ROS [15].…”

“…While the negative effects of DJ-1 on ferroptosis is not attributed to its classical role in stabilizing NRF2. DJ-1 suppresses ferroptosis triggered by lipid ROS through maintaining cysteine synthesized from the transsulfuration pathway, the predominant source of cysteine for GSH biosynthesis when the cystine/glutamate transporter (SLC7A11, xCT) is inhibited [14]. Moreover, the suppression of the DJ-1 expression dramatically enhanced the sensitivity to the ferroptosis inducer Erastin of tumour cells both in vitro and in vivo [14].…”

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

“…Because cysteine is a limiting component of GSH, cysteine levels control ferroptosis. It is thus likely that silencing CAT contributes to maintain cysteine available for ferroptosis inhibition [ 48 ]. Accordingly, Zhang et al showed that suppression of miRNA-9 increased the sensitivity of melanoma cells to ferroptosis-inducing drugs [ 46 ].…”