Abstract
Aberrant epigenetic modification induces oncogene expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates histone 3 lysine 4 (H3K4), is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study reported that SETD1A promotes gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. In this study, we found that overexpression of SETD1A promoted GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration and invasion in vitro. Moreover, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin, Vimentin, and α-smooth muscle actin (α-SMA). Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factor snail expression. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on the snail promoter. Furthermore, SETD1A could be a coactivator of snail to induce EMT gene expression. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, knockdown of SETD1A suppressed GC metastasis in vivo. In summary, our data revealed that SETD1A mediated the EMT process and induced metastasis through epigenetic reprogramming of snail.
Highlights
Gastric cancer (GC) is a highly lethal malignant tumor in the digestive system (Cao et al, 2021; Siegel et al, 2021; Sung et al, 2021)
SETD1A cDNAs were transfected into gastric cancer (GC) cells BGC-803 and AGS to increase the expression of SETD1A and determine the migration and invasion abilities of BGC803 and AGS cells
B, overexpression of SETD1A increased the migration and invasion abilities of BGC-823 and AGS cells. These results indicate that upregulation of SETD1A could enhance GC cell migration and invasion
Summary
Gastric cancer (GC) is a highly lethal malignant tumor in the digestive system (Cao et al, 2021; Siegel et al, 2021; Sung et al, 2021). More efforts are mandatorily needed to develop novel GC therapeutic strategies for treatment of GC metastasis. Epithelial-mesenchymal transition (EMT), first discovered in embryonic development, can induce epithelial cells to acquire a mesenchymal phenotype (Bakir et al, 2020). EMT represents one of the most lethal features of the tumor, metastasis, and, determines an attractive therapy target in cancer, including GC, prostate, hepatocellular, and colorectal cancers (Huang et al, 2015; Cheaito et al, 2019, 2020; Abed Kahnamouei et al, 2020; Hu et al, 2020; Ramesh et al, 2020; Wang et al, 2020). Identifying novel mediators of EMT might help in defining new therapeutic targets and, novel potential cancer therapies. Our aim is to explore novel molecular markers of EMT and reveal the potential mechanism resulting in GC metastasis
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