Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, MD, USA.
Nat Commun. 2018 Jul 9;9(1):2372. doi: 10.1038/s41467-018-04590-1.
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
Hippo 信号通路的失调和随之而来的 YAP1 激活是人类恶性肿瘤中常见的事件，但潜在的分子机制仍知之甚少。对核心 Hippo 激酶及其候选调节分子的泛癌症分析显示，经典 Hippo 通路中很少有改变，但在非典型钙黏蛋白的 FAT 家族中经常发生遗传改变。通过专注于头颈部鳞状细胞癌（HNSCC），其显示出频繁的 FAT1 改变（29.8%），我们提供了证据表明 FAT1 功能丧失导致 YAP1 激活。从机制上讲，我们发现 FAT1 组装了一个多聚 Hippo 信号复合物（信号组），导致 TAOKs 激活核心 Hippo 激酶，随后 YAP1 失活。我们还表明，不受限制的 YAP1 是 HNSCC 的致癌驱动因素，针对 YAP1 可能是携带 FAT1 肿瘤抑制基因基因组改变的癌症的一种有吸引力的精准治疗选择。
