A novel EZH1/2 dual inhibitor inhibits GCB DLBCL through Cell Cycle Regulation and M2 Tumor-Associated Macrophage Polarization
The incidence of germinal center B-cell-like diffuse large B-cell lymphoma (GCB DLBCL) is on the rise, and there is a recognized hereditary component to the disease. While some molecular mechanisms underlying GCB DLBCL have been identified, our understanding remains incomplete, hindering the success of targeted therapies. In patients with GCB DLBCL, elevated expression of zeste homolog 2 (EZH2) has been observed, and the compensatory activation of EZH1 after EZH2 inhibition contributes to poor patient outcomes. This suggests that dual inhibition of EZH1 and EZH2 may offer a promising therapeutic PF-06821497 approach. In this study, we developed a novel dual inhibitor, EZH-1-P2, targeting both EZH1 and EZH2, and assessed its anti-tumor effects on DLBCL cells. Mechanistically, inhibiting EZH1/2 disrupts epigenetic regulation of p53-related gene expression, affecting cell cycle progression and the growth of GCB DLBCL cells. Additionally, although EZH1/2 inhibition influences NOTCH signaling, further investigation is required to clarify how it impacts M2-type tumor-associated macrophage (M2-TAM) polarization and germinal center expansion. Our findings introduce EZH-1-P2 as a novel therapeutic candidate for GCB DLBCL, though more research is needed to fully understand its mechanisms.