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AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis.
Oncogene ( IF 6.9 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41388-020-1293-5 Yuhang Zhou 1, 2, 3 , Jinglin Zhang 1, 2, 3 , Hui Li 1 , Tingting Huang 1, 2, 3 , Chi Chun Wong 2 , Feng Wu 1 , Man Wu 1 , Nuoqing Weng 4 , Liping Liu 5 , Alfred S L Cheng 6 , Jun Yu 2, 7 , Nathalie Wong 1, 3 , Kwok Wai Lo 1, 3 , Patrick M K Tang 1 , Wei Kang 1, 2, 3 , Ka Fai To 1, 2, 3
Oncogene ( IF 6.9 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41388-020-1293-5 Yuhang Zhou 1, 2, 3 , Jinglin Zhang 1, 2, 3 , Hui Li 1 , Tingting Huang 1, 2, 3 , Chi Chun Wong 2 , Feng Wu 1 , Man Wu 1 , Nuoqing Weng 4 , Liping Liu 5 , Alfred S L Cheng 6 , Jun Yu 2, 7 , Nathalie Wong 1, 3 , Kwok Wai Lo 1, 3 , Patrick M K Tang 1 , Wei Kang 1, 2, 3 , Ka Fai To 1, 2, 3
Affiliation
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Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1-YAP1-CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1-CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.
中文翻译：
AMOTL1增强YAP1稳定性并促进YAP1驱动的胃癌发生。
河马信号的功能是限制细胞的生长，但是其下游YAP1的异常核积累导致癌变。YAP1 / TEAD复合物激活致癌下游转录，如CTGF和c-Myc。如何保护YAP1在细胞质中免受泛素介导的降解仍然是未知的。在这项研究中，通过几个临床队列筛选出血管动蛋白（Motin）家族成员AMOTL1（血管动蛋白样1）是唯一促进YAP1核积累的分子，细胞功能测定进一步证实了这一点。通过共免疫沉淀和免疫荧光染色提示YAP1和AMOTL1之间的相互作用。通过多个临床队列分析了AMOTL1-YAP1-CTGF轴在胃癌（GC）中的临床意义。此外，通过药物敏感性试验和异种移植物形成试验评估了靶向致癌轴的治疗效果。AMOTL1的上调与GC的不良临床结果相关，而降低AMOTL1的表达会损害其致癌特性。AMOTL1和YAP1之间的细胞质相互作用可保护彼此免受泛素介导的降解。AMOTL1促进YAP1易位进入细胞核以激活下游表达，如CTGF。剔除AMOTL1，YAP1和CTGF可提高一线抗癌药物的治疗效果。总之，AMOTL1通过与YAP1相互作用并促进其核蓄积在胃癌发生中起着致癌作用。AMOTL1，YAP1和CTGF表达的组合可能代表了Hippo激活状态。
更新日期：2020-04-24
中文翻译：
AMOTL1增强YAP1稳定性并促进YAP1驱动的胃癌发生。
河马信号的功能是限制细胞的生长，但是其下游YAP1的异常核积累导致癌变。YAP1 / TEAD复合物激活致癌下游转录，如CTGF和c-Myc。如何保护YAP1在细胞质中免受泛素介导的降解仍然是未知的。在这项研究中，通过几个临床队列筛选出血管动蛋白（Motin）家族成员AMOTL1（血管动蛋白样1）是唯一促进YAP1核积累的分子，细胞功能测定进一步证实了这一点。通过共免疫沉淀和免疫荧光染色提示YAP1和AMOTL1之间的相互作用。通过多个临床队列分析了AMOTL1-YAP1-CTGF轴在胃癌（GC）中的临床意义。此外，通过药物敏感性试验和异种移植物形成试验评估了靶向致癌轴的治疗效果。AMOTL1的上调与GC的不良临床结果相关，而降低AMOTL1的表达会损害其致癌特性。AMOTL1和YAP1之间的细胞质相互作用可保护彼此免受泛素介导的降解。AMOTL1促进YAP1易位进入细胞核以激活下游表达，如CTGF。剔除AMOTL1，YAP1和CTGF可提高一线抗癌药物的治疗效果。总之，AMOTL1通过与YAP1相互作用并促进其核蓄积在胃癌发生中起着致癌作用。AMOTL1，YAP1和CTGF表达的组合可能代表了Hippo激活状态。
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