1. Academic Validation
  2. SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression

SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression

  • J Pathol. 2021 Feb;253(2):148-159. doi: 10.1002/path.5568.
Wenjing Shang 1 2 Yue Wang 1 Xiuming Liang 1 3 Tongyu Li 1 Wei Shao 1 Fen Liu 1 Xiujie Cui 1 Yuanyuan Wang 1 Lin Lv 1 Li Chai 1 Lingxin Qu 1 Lixin Zheng 1 Jihui Jia 1 2 3
Affiliations

Affiliations

  • 1 Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
  • 2 Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
  • 3 Shandong University-Karolinska Institute Collaborative Laboratory for Cancer Research, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
Abstract

SETDB1 is a histone lysine methyltransferase that has critical roles in cancers. However, its potential role in gastric Cancer (GC) remains obscure. Here, we mainly investigate the clinical significance and the possible role of SETDB1 in GC. We find that SETDB1 expression is upregulated in GC tissues and its high-level expression was a predictor of poor prognosis in patients. Overexpression of SETDB1 promoted cell proliferation and metastasis, while SETDB1 suppression had an opposite effect both in vitro and in vivo. Mechanistically, SETDB1 was shown to interact with ERG to promote the transcription of cyclin D1 (CCND1) and matrix metalloproteinase 9 (MMP9) through binding to their promoter regions. In addition, the expression of SETDB1 was also enhanced by the transcription factor TCF4 at the transcriptional level in GC. Furthermore, SETDB1 expression was found to be induced by Helicobacter pylori (H. pylori) Infection in a TCF4-dependent manner. Taken together, our results indicate that SETDB1 is aberrantly overexpressed in GC and plays key roles in gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9. Our work also suggests that SETDB1 could be a potential oncogenic factor and a therapeutic target for GC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords

CCND1; ERG; Helicobacter pylori; MMP9; SETDB1; TCF4; gastric cancer; histone methyltransferase; invasion; proliferation.

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