Dasgupta Maupali, Dermawan Josephine Kam Tai, Willard Belinda, Stark George R
Department of Molecular Genetics and.
Department of Molecular Genetics and
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):3985-90. doi: 10.1073/pnas.1503152112. Epub 2015 Mar 12.
Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers. Connecting EZH2 to a functionally important methylation of STAT3, which is constitutively activated in many tumors, may help reveal the basis of the opposing roles of EZH2 in liquid and solid tumors and also may identify novel therapeutic opportunities.
包括p53、NF-κB和STAT3在内的几种转录因子会被同样能修饰组蛋白的酶所修饰,从而产生重要的功能后果。我们发现了STAT3第49位赖氨酸的一种此前未被识别的二甲基化,它对于许多白细胞介素-6依赖性基因的表达至关重要,由组蛋白修饰酶zeste同源物2增强子(EZH2)催化。EZH2的缺失在白血病中具有促肿瘤作用,但其过表达在实体癌中具有促肿瘤作用。将EZH2与STAT3的一种功能上重要的甲基化联系起来,而STAT3在许多肿瘤中是组成性激活的,这可能有助于揭示EZH2在液体肿瘤和实体肿瘤中相反作用的基础,也可能识别出新的治疗机会。