Abstract
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 in vitro 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.
Highlights
Gastric cancer (GC) is one of the most lethal malignancies worldwide and has a high mortality rate in East Asian countries, especially in China and Japan [1]
We newly determine that nucleolar spindle-associated protein 1 (NUSAP1) functions as a positive regulator of YAP1 to facilitate gastric cancer (GC) tumorigenesis and progression
With regard to the molecular mechanism, we discovered for the first time that NUSAP1 enhances YAP1 protein stability by physically interacting with YAP1
Summary
Gastric cancer (GC) is one of the most lethal malignancies worldwide and has a high mortality rate in East Asian countries, especially in China and Japan [1]. Despite great progress in surgical and comprehensive therapies, improvements in the clinical outcomes of patients with GC remain limited [2]. It is of utmost importance to explore the molecular mechanism underlying GC tumorigenesis and progression and to identify new therapeutic targets for patients with GC. The core Hippo pathway consists of a kinase cascade: the upstream kinase MST1/2 phosphorylates and activates the downstream kinase LATS1/2, leading to phosphorylation and inactivation of the transcriptional coactivator Yesassociated protein (YAP1) [4,5,6]. The phosphorylated YAP1 translocates to the nucleus and associates with transcription factors, such as the TEA domain (TEAD) family, RUNX, and SMADs [7,8,9], favoring an accelerated rate of cell growth, invasiveness, and survival
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