NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein

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.

Effect of MiR-375 Regulates YAP1 on the Invasion, Apoptosis, and Epithelial-Mesenchymal Transition of Cervical Cancer HeLa Cells

“…YAP1 is the main effector molecule in the signal pathway Hippo-YAP, which plays an important role in regulating cell proliferation, invasion, apoptosis, and malignant transformation. Studies have shown that YAP1 is highly expressed in malignant tumors such as gastric cancer [ 4 ], laryngeal cancer [ 17 ], and triple negative breast cancer [ 18 ]. The results of this study showed that the expression of YAP1 in cervical cancer cells HeLa increased.…”

“…MicroRNA (microRNA, miRNA) is abnormally expressed in a variety of malignant tumors and participates in the occurrence and metastasis of malignant tumors. MiRNAs with abnormally elevated expression accelerate tumorigenesis by inhibiting tumor suppressor factors, and miRNAs with reduced expression inhibit tumorigenesis by negatively regulating the expression of oncogenes [ 3 , 4 ]. miR-375 has been confirmed to be related to the occurrence of cervical cancer.…”

The E3 Ubiquitin Ligase TRIM11 Facilitates Gastric Cancer Progression by Activating the Wnt/β-Catenin Pathway via Destabilizing Axin1 Protein

“…Puromycin (final concentration: 2 μg/mL) was used to select stable MKN-45 cells overexpressing TRIM11 for two weeks. All the transfection or infection experiments were performed using the transfection reagent TurboFect ( ermo Scientific, R0532, USA) as previously described [26,27].…”

Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic lymphocytic leukemia by binding with RAD51

“…Nucleolar and spindle-associated protein 1 (NUSAP1), with a molecular weight of 55KD, serves as a microtubule-binding protein in chromosome separation, spindle assembly, and plays significant role to ensure normal regulation of cell cycle as well [ 5 ]. Previous studies suggested that NUSAP1 was abnormally elevated in numerous tumors including liver cancer [ 6 ], breast cancer [ 7 ], prostate cancer [ 8 ], gastric cancer [ 9 ], and bladder cancer [ 10 ]. High expression of NUSAP1 correlates with the adverse prognosis of cervical cancer [ 11 ] and breast cancer [ 7 ].…”

“…High expression of NUSAP1 correlates with the adverse prognosis of cervical cancer [ 11 ] and breast cancer [ 7 ]. In addition, NUSAP1 engages in the biological process such as cell proliferation, apoptosis, cell cycle and metastasis in several types of cancers by regulating Wnt/β-catenin [ 12 ], Hedgehog [ 13 ], PI3K/AKT [ 14 ], Hippo-Yap1 [ 9 ], and other pathways. It was reported that NUSAP1 participated in the cellular DNA damage response process [ 15 ].…”