Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
复制标题
DOI：
10.1016/j.celrep.2019.10.083
复制
发表时间：
2019-11-19
期刊：
影响因子：
8.8
通讯作者：
Uchimaru, Kaoru
中科院分区：
文献类型：
--
作者：
Yamagishi, Makoto;Hori, Makoto;Uchimaru, Kaoru
尽管全局H3 K27 me 3重编程是癌症的标志，但尚未建立针对携带EZH 2（WT/WT）的H3 K27 me 3高恶性肿瘤的有效治疗策略。我们探索了EZH 2（WT/WT）和EZH 2（WT/Mu）侵袭性淋巴瘤的表观基因组和转录组，并表明共表达的EZH 1和EZH 2的相互干扰和补偿功能重新排列了它们自己的全基因组分布，从而建立了限制性染色质和基因表达特征。主要化合物的直接比较介绍了EZH 1/2双重抑制剂（valemetostat）的效力和作用机制。在所有淋巴瘤模型和原发性成人T细胞白血病-淋巴瘤（ATL）细胞中观察到合成致死性。EZH 1/2-polycomb和SWI/SNF复合物的相反作用是兼性异染色质形成所必需的。染色质相关基因（ARID 1A、SMARCA 4/BRG 1、SMARCB 1/SNF 5、KDM 6A/UTX、BAP 1、KMT 2D/MLL 2）的失活和肿瘤病毒感染（HTLV-1、EBV）触发EZH 1/2扰动和H3 K27 me 3沉积。我们的研究为EZH 1/2在癌症表观基因组中的化学双重靶向提供了基于机制的理论基础。
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2(WT/WT) has yet been established. We explore epigenome and transcriptome in EZH2(WT/WT) and EZH2(WT/Mu) aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome.