Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H3K27me3), leading to the repression of gene expression. Although previous reports suggest EZH2 as an effective therapeutic target, the functions of EZH1, the other homolog of EZH, in MRT remain unknown. Here, we show that EZH1, as well as EZH2, contributes to MRT cell growth and H3K27 methylation. Depletion or selective inhibition of EZH2 led to a compensatory increase in EZH1 expression, and depletion of EZH1 enhanced the effect of EZH2 inhibition. EZH1/2 dual inhibitors suppressed MRT cell growth markedly, reflecting the reduction of H3K27me3 accumulation at one of the EZH1/2 targets, the CDKN2A locus. Dual inhibition of EZH1/2 in vivo suppressed tumor growth completely, with no significant adverse effects. These findings indicate that both EZH1 and EZH2 are potential targets for MRT therapy, and that EZH1/2 dual inhibitors may be promising therapeutic strategies for MRT.

恶性横纹肌瘤 (MRT) 是一种罕见且高度侵袭性的儿科癌症，没有标准的护理。MRT 的特征在于 SMARCB1 的缺失，这导致 zeste 同源物 2 (EZH2) 增强子的表达上调，该增强子负责组蛋白 H3 (H3K27me3) 的赖氨酸 27 的甲基化，从而导致基因表达的抑制。尽管先前的报道表明 EZH2 是一种有效的治疗靶点，但 EZH1（EZH 的另一个同源物）在 MRT 中的功能仍然未知。在这里，我们显示 EZH1 以及 EZH2 有助于 MRT 细胞生长和 H3K27 甲基化。EZH2的消耗或选择性抑制导致EZH1表达的补偿性增加，并且EZH1的消耗增强了EZH2抑制的作用。EZH1/2双重抑制剂显着抑制MRT细胞生长，CDKN2A基因座。在体内对 EZH1/2 的双重抑制完全抑制了肿瘤的生长，没有明显的副作用。这些发现表明 EZH1 和 EZH2 都是 MRT 治疗的潜在靶点，并且 EZH1/2 双抑制剂可能是 MRT 的有希望的治疗策略。