Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
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Sp1-Induced SETDB1 Overexpression Transcriptionally Inhibits HPGD in a β-Catenin-Dependent Manner and Promotes the Proliferation and Metastasis of Gastric Cancer

  • Fan, Yaguan (Department of Medical Oncology, The First People's Hospital of Yunnan Province) ;
  • Yang, Libo (Department of Medical Oncology, The First People's Hospital of Yunnan Province) ;
  • Ren, Yi (Department of Medical Oncology, The First People's Hospital of Yunnan Province) ;
  • Wu, Yunhua (Department of Medical Oncology, The First People's Hospital of Yunnan Province) ;
  • Li, Linhai (Department of General Surgery, The First People's Hospital of Yunnan Province) ;
  • Li, Lihua (Department of Medical Oncology, The First People's Hospital of Yunnan Province)
  • Received : 2022.05.16
  • Accepted : 2022.07.14
  • Published : 2022.10.31
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Abstract

Purpose: Gastric cancer (GC) has high morbidity and mortality, the cure rate of surgical treatment and drug chemotherapy is not ideal. Therefore, development of new treatment strategies is necessary. We aimed to identify the mechanism underlying Sp1 regulation of GC progression. Methods and Methods: The levels of Sp1, β-catenin, SET domain bifurcated 1 (SETDB1), and 15-hydroxyprostaglandin dehydrogenase (HPGD) were detected by quantitative reverse transcription polymerase chain reaction and western blot analysis. The targets of SETDB1 were predicted by AnimalTFDB, and dual-luciferase reporter assay was used for confirming the combination of Sp1, β-catenin, and SETDB1. HGC27 or AGS cells (1×106 cells/mouse) were injected into mice via the caudal vein for GC model establishment. The level of Ki67 was detected using immunohistochemistry, and hematoxylin and eosin staining was performed for evaluating tumor metastasis in mice with GC. Results: HPGD was inhibited, while the protein levels of Sp1, β-catenin, and SETDB1 were up-regulated in GC tissues and cell lines. HPGD overexpression or SETDB1 silencing inhibited the proliferation, invasion, and migration of GC cells, and Sp1 regulated the proliferation, invasion, and migration of GC cells in a β-catenin-dependent manner. Furthermore, HPGD served as a target of SETDB1, and it was negatively regulated by SETDB1; additionally, Sp1 and β-catenin bound to the SETDB1 promoter and negatively regulated HPGD expression. We proved that Sp1 regulated GC progression via the SETDB1/HPGD axis. Conclusions: Our findings revealed that Sp1 transcriptionally inhibited HPGD via SETDB1 in a β-catenin-dependent manner and promoted the proliferation and metastasis of GC cells.

Keywords

Acknowledgement

We would like to express our sincere gratitude to the reviewers for their constructive comments.

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