The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.
The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.
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DOI：
10.1016/j.celrep.2018.12.059
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发表时间：
2019-01
期刊：
影响因子：
8.8
通讯作者：
Qionghua Zhu;L. Fang;Julian Heuberger;A. Kranz;J. Schipper;K. Scheckenbach;R. Vidal;D. Sunaga-Franze;M. Müller;A. Wulf‐Goldenberg;S. Sauer;W. Birchmeier
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文献类型：
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作者：
Qionghua Zhu;L. Fang;Julian Heuberger;A. Kranz;J. Schipper;K. Scheckenbach;R. Vidal;D. Sunaga-Franze;M. Müller;A. Wulf‐Goldenberg;S. Sauer;W. Birchmeier
我们确定了一种在唾液腺和头颈癌中作用于Wnt/β-连环蛋白信号下游的调节系统。我们在K14-Cre诱导的Wnt/β-cateningain-of-function和Bmpr 1失功能突变的小鼠肿瘤模型中显示，肿瘤增殖细胞表现出Mll 1活性增加和启动子处全基因组H3 K4三甲基化增加。在肿瘤小鼠和异种移植的人头颈部肿瘤中，Mll 1的突变导致肿瘤增殖细胞自我更新的丧失和肿瘤形成的阻断，但不改变正常组织的稳态。CRISPR/Cas9诱变和Mll 1在抑制必需蛋白质-蛋白质相互作用或SET酶活性位点的序列处的药理学干扰也阻断了小鼠和人肿瘤增殖细胞的自我更新。我们的工作为Mll 1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Mll 1相互作用的抑制剂可能为治疗这些侵袭性肿瘤的疗法提供额外的方向。
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-inducedWnt/β-cateningain-of-function andBmpr1aloss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations ofMll1in 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.