Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin 300052, China.
Int J Mol Sci. 2023 May 11;24(10):8603. doi: 10.3390/ijms24108603.
EZH2, a member of the polycomb repressive complex 2, induces trimethylation of the downstream gene at the histone three lysine 27 (H3K27me3) position to inhibit tumor cell proliferation. Here, we showed that the apoptosis rate and apoptotic protein expression increased after EZH2 inhibition, whereas key molecules of the NF-κB signaling pathway and the downstream target genes were inhibited. Additionally, the expression of CD155, a TIGIT high-affinity ligand in multiple myeloma (MM) cells, was decreased by the mTOR signaling pathway. Furthermore, the combination of EZH2 inhibitor and TIGIT monoclonal antibody blockade enhanced the anti-tumor effect of natural killer cells. In summary, the EZH2 inhibitor not only plays an anti-tumor role as an epigenetic drug, but also enhances the anti-tumor effect of the TIGIT monoclonal antibody by affecting the TIGIT-CD155 axis between NK cells and MM cells, thus providing new ideas and theoretical basis for the treatment of MM patients.
EZH2 是 polycomb 抑制复合物 2 的成员，可诱导下游基因在组蛋白 3 赖氨酸 27（H3K27me3）位置的三甲基化，从而抑制肿瘤细胞增殖。在这里，我们表明 EZH2 抑制后凋亡率和凋亡蛋白表达增加，而 NF-κB 信号通路的关键分子和下游靶基因受到抑制。此外，多发性骨髓瘤（MM）细胞中 TIGIT 的高亲和力配体 CD155 的表达被 mTOR 信号通路下调。此外，EZH2 抑制剂和 TIGIT 单克隆抗体阻断的联合使用增强了自然杀伤细胞的抗肿瘤作用。总之，EZH2 抑制剂不仅作为一种表观遗传药物发挥抗肿瘤作用，还通过影响 NK 细胞和 MM 细胞之间的 TIGIT-CD155 轴增强 TIGIT 单克隆抗体的抗肿瘤作用，为 MM 患者的治疗提供了新的思路和理论依据。
