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

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.

Integrative analysis of small non-coding RNAs predicts a piRNA/miRNA-CCND1/BRAF/HRH1/ATXN3 regulatory circuit that drives oncogenesis in glioblastoma

“…55 Another study has revealed the association between ccnd1 and setdb1 in gastric cancer, where the upregulation of setdb1 could affect the metastasis via upregulation of ccnd1 and mmp9 . 56…”

“…55 Another study has revealed the association between ccnd1 and setdb1 in gastric cancer, where the upregulation of setdb1 could affect the metastasis via upregulation of ccnd1 and mmp9. 56 Moreover, a few studies have reported the relationship between CCND1 and BRAF, which are the key components of the MAP kinase pathway. CCND1 amplification was associated with BRAF activation mutation in human melanoma.…”

Increased Expression of SETDB1 Predicts Poor Prognosis in Multiple Myeloma

“…Yu et al found that upregulation of SETDB1 enhanced the transcription of CCND1 and CDK6, thereby promoting proliferation of colorectal cancer cells [ 44 ]. Shang et al observed that high SETDB1 expression may accelerate cell proliferation through the ERG-CCND1/MMP9 axis, which was also associated with adverse prognosis in gastric cancer [ 45 ]. Hence, it has been demonstrated that SETDB1 may regulate the cell cycle genes leading to disease progression in multiple myeloma.…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…found that the trimethylated state of H3K9 is highly expressed and positively correlated with tumor staging 239,240 . SETDB1 is abnormally overexpressed in GC and plays a crucial role in GC occurrence and metastasis by upregulating β‐catenin and matrix metalloproteinase 9 241,242 . Furthermore, in the xenograft tumor model, the knockout methyltransferase G9a showed a concomitant marked reduction in H3K9 monomethylation and potent inhibition of mechanistic target of rapamycin (mTOR) expression and tumor growth 243 .…”