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Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-Jun-01 , DOI: 10.1038/s41591-018-0034-6
Lu Wang , Zibo Zhao , Patrick A. Ozark , Damiano Fantini , Stacy A. Marshall , Emily J. Rendleman , Kira A. Cozzolino , Nundia Louis , Xingyao He , Marc A. Morgan , Yoh-hei Takahashi , Clayton K. Collings , Edwin R. Smith , Panagiotis Ntziachristos , Jeffrey N. Savas , Lihua Zou , Rintaro Hashizume , Joshua J. Meeks , Ali Shilatifard

The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.

中文翻译:

重置Polycomb的表观遗传平衡和COMPASS在癌症治疗增强剂上的功能。

赖氨酸甲基转移酶KMT2C(也称为MLL3),COMPASS复合物的亚基,在基因增强子上实现组蛋白H3(H3K4)上Lys4的单甲基化。KMT2C(以下称为MLL3)经常会在一系列人类肿瘤类型中引起点突变,但这些病变如何精确地改变MLL3功能并促进肿瘤发生尚不清楚。在这里,我们报告在编码其植物同源域(PHD)重复区域的MLL3中的癌症突变热点,并证明该域介导MLL3与组蛋白H2A去泛素酶和肿瘤抑制因子BAP1的关联。编码MLL3 PHD重复序列中与癌症相关的突变破坏了MLL3和BAP1之间的相互作用,并与较差的患者存活率相关。具有PHD相关MLL3突变或缺乏BAP1的癌细胞显示MLL3和H3K27脱甲基酶KDM6A(也称为UTX)向基因增强子的募集减少。结果,在具有BAP1或MLL3突变的肿瘤细胞中,Polycomb阻抑复合物2(PRC2)的H3K27甲基转移酶活性受到抑制,从而恢复了正常的基因表达模式,并损害了体内的细胞增殖。这项研究提供了对MLL3中PHD相关突变的致癌作用的机理研究,并表明恢复平衡状态的Polycomb-COMPASS活性可能对具有编码这些表观遗传因子基因突变的肿瘤具有治疗效果。抑制具有BAP1或MLL3突变的肿瘤细胞中的Polycomb阻抑复合物2(PRC2)的H3K27甲基转移酶活性,可恢复正常的基因表达方式并损害体内的细胞增殖。这项研究提供了对MLL3中PHD相关突变的致癌作用的机理研究,并表明恢复平衡状态的Polycomb-COMPASS活性可能对具有编码这些表观遗传因子基因突变的肿瘤具有治疗效果。抑制具有BAP1或MLL3突变的肿瘤细胞中的Polycomb阻抑复合物2(PRC2)的H3K27甲基转移酶活性,可恢复正常的基因表达方式并损害体内的细胞增殖。这项研究提供了对MLL3中PHD相关突变的致癌作用的机理研究,并表明恢复平衡状态的Polycomb-COMPASS活性可能对具有编码这些表观遗传因子基因突变的肿瘤具有治疗效果。
更新日期:2018-05-22
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