Chen Yaoyu, Chen Jinyun, Yu Jianjun, Yang Guizhi, Temple Emilia, Harbinski Fred, Gao Hui, Wilson Christopher, Pagliarini Raymond, Zhou Wenlai
From the Departments of Oncology.
the Department of Oncology, Novartis Institutes for Biomedical Research, Emeryville, California 94608.
J Biol Chem. 2014 Jul 4;289(27):18914-27. doi: 10.1074/jbc.M114.574053. Epub 2014 May 15.
Heat shock protein 90 (HSP90) inhibition inhibits cancer cell proliferation through depleting client oncoproteins and shutting down multiple oncogenic pathways. Therefore, it is an attractive strategy for targeting human cancers. Several HSP90 inhibitors, including AUY922 and STA9090, show promising effects in clinical trials. However, the efficacy of HSP90 inhibitors may be limited by heat shock factor 1 (HSF1)-mediated feedback mechanisms. Here, we identify, through an siRNA screen, that the histone H3 lysine 4 methyltransferase MLL1 functions as a coactivator of HSF1 in response to HSP90 inhibition. MLL1 is recruited to the promoters of HSF1 target genes and regulates their expression in response to HSP90 inhibition. In addition, a striking combination effect is observed when MLL1 depletion is combined with HSP90 inhibition in various human cancer cell lines and tumor models. Thus, targeting MLL1 may block a HSF1-mediated feedback mechanism induced by HSP90 inhibition and provide a new avenue to enhance HSP90 inhibitor activity in human cancers.
热休克蛋白90（HSP90）抑制通过消耗客户癌蛋白和关闭多个致癌途径来抑制癌细胞增殖。因此，它是一种针对人类癌症的有吸引力的策略。几种HSP90抑制剂，包括AUY922和STA9090，在临床试验中显示出有前景的效果。然而，HSP90抑制剂的疗效可能受到热休克因子1（HSF1）介导的反馈机制的限制。在此，我们通过小干扰RNA筛选确定，组蛋白H3赖氨酸4甲基转移酶MLL1在响应HSP90抑制时作为HSF1的共激活因子发挥作用。MLL1被招募到HSF1靶基因的启动子上，并响应HSP90抑制调节它们的表达。此外，在各种人类癌细胞系和肿瘤模型中，当MLL1缺失与HSP90抑制联合时，观察到显著的联合效应。因此，靶向MLL1可能阻断由HSP90抑制诱导的HSF1介导的反馈机制，并为增强HSP90抑制剂在人类癌症中的活性提供一条新途径。
