Search for


search for   

 

Synergistic Effects of Combined PROTAC-based EZH2 Degrader and METTL3 Inhibitor in Burkitt’s Lymphoma
Korean J Clin Lab Sci 2024;56:198-206  
Published on September 30, 2024
Copyright © 2024 Korean Society for Clinical Laboratory Science.

Minseo YU , Ra Eun KIM , Yurim JEONG , Hyewon JANG , Se Been KIM , Jung-Yeon LIM

Department of Biomedical Laboratory Science, Inje University, Gimhae, Korea
Correspondence to: Jung-Yeon LIM
Department of Biomedical Laboratory Science, Inje University, 197 Inje-ro, Gimhae 50834, Korea
E-mail: limjy@inje.ac.kr
ORCID: https://orcid.org/0000-0001-5903-8810
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords : Apoptosis, Burkitt’s lymphoma, Enhancer of zeste homolog 2 protein, METTL3 protein, Proteolysis targeting chimera

Full Text(PDF) Free

Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information