Guo Hui, Zou Jianping, Zhou Ling, Zhong Min, He Yan, Huang Shanshan, Chen Jun, Li Junhe, Xiong Jianping, Fang Ziling, Xiang Xiaojun
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Front Oncol. 2021 Jan 7;10:591698. doi: 10.3389/fonc.2020.591698. eCollection 2020.
The Yes-associated protein (YAP1) is a main effector of the canonical Hippo pathway, which contributes greatly to tumor initiation, progression, and metastasis in multiple cancers, including gastric cancer (GC). Due to limited knowledge of YAP1 upregulation in cancer, it is a great challenge of therapeutic targets toward the Hippo-YAP1 pathway. Here, we identify nucleolar spindle-associated protein 1 (NUSAP1) as a novel binding partner of YAP1. The upregulation of NUSAP1 is associated with unfavorable clinical outcomes in GC patients, and NUSAP1 depletion impairs its oncogenic properties and in a xenograft model. Mechanistically, we discovered that NUSAP1 functions as a positive regulator of YAP1 protein stability, thereby inducing the transcription of Hippo pathway downstream target genes, such as CTGF and CYR61. More interestingly, we find that the cancer-promoting effects of NUSAP1 on GC cell growth, migration, and invasion are mainly mediated by YAP1. Furthermore, aberrant expression of NUSAP1 and YAP1 is highly correlated in GC cell lines and tissues. We herein clarify the role of the oncogenic NUSAP1-YAP1 axis in GC tumorigenesis and progression and, therefore, provide novel therapeutic targets for GC treatment.
Yes相关蛋白（YAP1）是经典Hippo信号通路的主要效应因子，在包括胃癌（GC）在内的多种癌症的肿瘤起始、进展和转移中发挥着重要作用。由于对癌症中YAP1上调的了解有限，靶向Hippo-YAP1信号通路的治疗靶点面临巨大挑战。在此，我们鉴定出核仁纺锤体相关蛋白1（NUSAP1）是YAP1的一种新型结合伴侣。NUSAP1的上调与GC患者不良临床结局相关，在异种移植模型中，NUSAP1的缺失会损害其致癌特性。从机制上讲，我们发现NUSAP1作为YAP1蛋白稳定性的正向调节因子，从而诱导Hippo信号通路下游靶基因如CTGF和CYR61的转录。更有趣的是，我们发现NUSAP1对GC细胞生长、迁移和侵袭的促癌作用主要由YAP1介导。此外，NUSAP1和YAP1的异常表达在GC细胞系和组织中高度相关。我们在此阐明了致癌性NUSAP1-YAP1轴在GC肿瘤发生和进展中的作用，因此为GC治疗提供了新的治疗靶点。
