• Korean Journal of Clinical Laboratory Science
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• v.56 no.3
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• pp.198-206
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• 2024

EZH2 is a methyltransferase that is a critical target for lymphoma treatment. However, it is not yet widely used in clinical settings. PROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy aimed at eliminating proteins that have been a challenging target using conventional small molecules. In our previous research, we compared the small molecules-based EZH2 inhibitor used in clinical settings with a PROTAC-based EZH2 degrader. We found that the PROTAC-based degrader was significantly more effective. Building on this, we further investigated the effects of combining the PROTAC-based EZH2 degrader (dEZH2) with a METTL3 inhibitor, both of which have demonstrated effectiveness in inhibiting cell proliferation and inducing apoptosis in Burkitt's lymphoma. Using the CCK-8 assay, we found that both drugs, alone and in combination, significantly inhibited Daudi and Ramos cell growth in a dose-dependent manner. The combined treatment markedly suppressed cell proliferation and induced apoptosis, as confirmed by Annexin V/PI staining. Our results revealed G2/M phase arrest with a significant decrease in the G0/G1 phase by flow cytometry. Our study also showed increased levels of cleaved PARP, cleaved caspase-3, tumor protein p53 (TP53), and PUMA using the western blot technique, indicating enhanced p53-dependent apoptosis. Our findings suggest that the combination therapy of dEZH2 and iMETTL3 could be a promising approach in the treatment of Burkitt's lymphoma.

• BMB Reports
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• v.54 no.6
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• pp.305-310
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• 2021

Cereblon (CRBN) is a multi-functional protein that acts as a substrate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells.