Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany; Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen 518055, China; Medi-X Institute, SUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology (SUSTech), Shenzhen 518055, China.
Cell Rep. 2019 Jan 8;26(2):415-428.e5. doi: 10.1016/j.celrep.2018.12.059.
We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.
我们鉴定出一个调控系统，它在唾液腺和头颈部癌中作为 Wnt/β-连环蛋白信号的下游发挥作用。我们在 K14-Cre 诱导的 Wnt/β-连环蛋白功能获得和 Bmpr1a 功能丧失突变的小鼠肿瘤模型中显示，肿瘤增殖细胞表现出 Mll1 活性增加和启动子处全基因组 H3K4 三甲基化增加。肿瘤小鼠和异种移植的人类头颈部肿瘤中 Mll1 的缺失突变导致肿瘤增殖细胞的自我更新丧失和肿瘤形成受阻，但不改变正常组织的体内平衡。CRISPR/Cas9 诱变和在抑制必需的蛋白-蛋白相互作用或 SET 酶活性位点的 Mll1 序列上进行的药物干扰也阻断了小鼠和人类肿瘤增殖细胞的自我更新。我们的工作为 Mll1 在实体瘤中的关键作用提供了强有力的遗传证据。此外，针对特定 Mll1 相互作用的抑制剂可能为治疗这些侵袭性肿瘤的治疗提供额外的方向。
