USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/LDHA axis

by Selleckchem | Jun 13 2023

The effect of aerobic glycolysis remains elusive in pediatric acute T lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of deubiquitination is involved in glycolysis, by targeting glycolytic rate-limiting enzymes. Here, we demonstrated that upregulated deubiquitinase USP1 expression correlated with poor prognosis in pediatric primary T-ALL samples. USP1 depletion abolished cellular proliferation and attenuated glycolytic metabolism. In vivo experiments showed that USP1 suppression decreased leukemia progression in nude mice. Inhibition of USP1 caused a decrease of both mRNA and protein levels in LDHA, a critical glycolytic enzyme. Moreover, USP1 interacted with and deubiquitinated PLK1, a critical regulator of glycolysis. Overexpression of USP1 with upregulated PLK1 was observed in most T-ALL patient samples. In addition, PLK1 inhibition reduced LDHA expression and abrogated the USP1-mediated increase of cell proliferation and lactate level. Ectopic expression of LDHA can rescue the suppressive effect of USP1 silencing on cell growth and lactate production. Pharmacological inhibition of USP1 by ML323 exhibited cell cytotoxicity in human T-ALL cells. Taken together, our results demonstrated that USP1 may be a promising therapeutic target in pediatric T-ALL.

Comments:

The passage describes a study conducted to investigate the role of aerobic glycolysis and deubiquitination in pediatric acute T lymphoblastic leukemia (T-ALL). The researchers focused on the deubiquitinase enzyme called USP1 and its correlation with prognosis in pediatric T-ALL patients. Here are the key findings and conclusions from the study:

Increased expression of USP1 was associated with poor prognosis in pediatric T-ALL patients.

Depletion of USP1 led to a decrease in cellular proliferation and attenuated glycolytic metabolism. In vivo experiments using nude mice demonstrated that suppressing USP1 reduced leukemia progression. Inhibition of USP1 resulted in decreased mRNA and protein levels of LDHA, a crucial enzyme involved in glycolysis.

USP1 was found to interact with and deubiquitinate PLK1, an important regulator of glycolysis.Most T-ALL patient samples exhibited elevated expression of both USP1 and PLK1.Inhibition of PLK1 reduced LDHA expression and reversed the USP1-mediated increase in cell proliferation and lactate production.

Ectopic expression of LDHA rescued the suppressive effect of USP1 silencing on cell growth and lactate production.Pharmacological inhibition of USP1 using a compound called ML323 exhibited cytotoxic effects on human T-ALL cells.

Based on these findings, the researchers concluded that USP1 could be a promising therapeutic target for pediatric T-ALL.

Overall, this study provides evidence that targeting USP1, which interacts with PLK1 and regulates LDHA expression, may offer a potential therapeutic approach for pediatric T-ALL. Inhibition of USP1 could attenuate glycolytic metabolism, reduce cell proliferation, and potentially impede leukemia progression.