The overexpression of glutathione peroxidase 4 (GPX4; an enzyme that suppresses peroxidation of membrane phospholipids) is considered a poor prognostic predictor of diffuse large B-cell lymphoma (DLBCL). However, the mechanisms employed in GPX4 overexpression remain unknown. GPX4 is translated as a complete protein upon the binding of SECISBP2 to the selenocysteine insertion sequence (SECIS) on the 3′UTR of GPX4 mRNA. In this study, we investigated the expression of SECISBP2 and its subsequent regulation of GPX4 and TXNRD1 in DLBCL patients. Moreover, we determined the significance of the expression of these selenoproteins in vitro using MD901 and Raji cells. SECISBP2 was positive in 45.5% (75/165 cases) of DLBCL samples. The SECISBP2-positive group was associated with low overall survival (OS) as compared to the SECISBP2-negative group (P = 0.006). Similarly, the SECISBP2 and GPX4 or TXNRD1 double-positive groups (P < 0.001), as well as the SECISBP2, GPX4, and TXNRD1 triple-positive group correlated with poor OS (P = 0.001), suggesting that SECISBP2 may serve as an independent prognostic predictor for DLBCL (hazard ratio (HR): 2.693, P = 0.008). In addition, western blotting showed a decrease in GPX4 and TXNRD1 levels in SECISBP2-knockout (KO) MD901 and Raji cells. Oxidative stress increased the accumulation of reactive oxygen species in SECISBP2-KO cells (MD901; P < 0.001, Raji; P = 0.020), and reduced cell proliferation (MD901; P = 0.001, Raji; P = 0.030), suggesting that SECISBP2-KO suppressed resistance to oxidative stress. Doxorubicin treatment increased the rate of cell death in SECISBP2-KO cells (MD901; P < 0.001, Raji; P = 0.048). Removal of oxidative stress inhibited the altered cell death rate. Taken together, our results suggest that SECISBP2 may be a novel therapeutic target in DLBCL.
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This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 18K07063).
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Taguchi, T., Kurata, M., Onishi, I. et al. SECISBP2 is a novel prognostic predictor that regulates selenoproteins in diffuse large B-cell lymphoma. Lab Invest (2020). https://doi.org/10.1038/s41374-020-00495-0