Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden.
Cell Death Dis. 2021 Feb 12;12(2):167. doi: 10.1038/s41419-021-03447-8.
Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.
多发性骨髓瘤（MM）是一种异质性血液疾病，临床治疗仍然具有挑战性。表观遗传沉默剂 EZH2 的活性增加是预后不良患者的共同特征。先前的研究结果表明，代谢谱可以作为癌症治疗反应的敏感标志物。虽然 EZH2 抑制（EZH2i）已被证明可有效诱导多种人类 MM 细胞系的细胞死亡，但我们在此确定了一小部分细胞系，尽管 H3K27me3 被全局丧失，但在 EZH2i 后仍然存活。通过将液相色谱-质谱与基因和 miRNA 表达谱相结合，我们发现对 EZH2i 的敏感性与由于参与蛋氨酸循环的基因失调而导致的不同代谢特征相关。具体而言，EZH2i 导致响应细胞中与蛋氨酸循环相关的基因的 miRNA 介导下调。这诱导了代谢物的积累和 DNA 损伤，导致 G2 期阻滞和细胞凋亡。总之，我们揭示了人类 MM 细胞系对 EZH2i 的敏感性与治疗后特定的代谢和基因表达谱相关。
