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Targeting NUF2 suppresses gastric cancer progression through G2/M phase arrest and apoptosis induction
Bo Long1, Huinian Zhou1, Lixia Xiao1
1The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China.
Background:
Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2 , a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression.
Methods:
Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021. Cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2 -associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC.
Results:
NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro . NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models.
Conclusions:
Collectively, NUF2 -mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.
Insights
NUF2 promotes gastric cancer (GC) progression by regulating cell cycle and inhibiting apoptosis. Targeting NUF2 with inhibitors like quercetin shows potent anti-GC activity, offering a new therapeutic strategy for this deadly disease.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Gastric cancer (GC) is a leading cause of cancer-related deaths globally, necessitating novel therapeutic targets.
- NUF2, a component of the NDC80 kinetochore complex, is implicated in promoting cancer progression across various malignancies.
Purpose of the Study:
- To investigate the role of NUF2 in gastric cancer progression.
- To evaluate NUF2 as a potential therapeutic target for inhibiting GC growth.
Main Methods:
- Analysis of clinical GC samples and patient-derived xenografts (PDX).
- In vitro and in vivo assays including cell counts, colony formation, flow cytometry, and live-cell imaging.
- Transcriptomics, virtual docking, and microscale thermophoresis to identify NUF2 inhibitors.
Main Results:
- Elevated NUF2 expression in GC correlates with poor prognosis.
- NUF2 deletion suppressed GC progression; NUF2 regulates the MAPK pathway, promotes G2/M phase transition, and inhibits apoptosis.
- Quercetin identified as a selective NUF2 inhibitor with low toxicity, significantly suppressing tumor growth in preclinical models.
Conclusions:
- NUF2-mediated G2/M phase transition and apoptosis inhibition drive GC progression.
- NUF2 inhibitors demonstrate significant anti-GC activity.
- Targeting NUF2 presents a promising new strategy for clinical GC treatment.
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