Abstract
BackgroundDAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown.MethodsWe analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models.ResultsDAXX was downregulated in advanced gastric cancer samples. The expression of DAXX inversely correlates with that of cancer stem cell markers CD44 and Oct4 in gastric cancer lines. DAXX overexpression in gastric cancer cells inhibited migration, invasion and epithelial– mesenchymal transition (EMT). The inhibition of EMT was achieved through the repression of SNAI3, a key inducer of EMT, by recruiting HDAC-1 into the nucleus. Using a xenograft mouse model, we demonstrated that the MKN45 cells formed smaller tumours when DAXX was overexpressed. Wild-type AGS cells were not able to form tumours in nude mice, but in contrast, formed visible tumours when DAXX was silenced in the cells.ConclusionWe for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.
Highlights
DAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown
DAXX is downregulated in advanced gastric cancer DAXX expression in clinical samples of different stages was examined by Western blot (Fig. 1)
The results showed that the two sequences of 832–1110 bp and 1972–2267 bp upstream of SNAI3 are enriched on H3K14ac in MKN45 cells, and the enrichment was reduced when DAXX was overexpressed (Fig. 5m), suggesting that DAXX inhibits the expression of SNAI3 by downregulating the acetylation level of H3K14 in gastric cancer cells
Summary
Death domain-associated protein (DAXX) is a transcription repressor involved in both physiological and pathological conditions. Previous studies showed that high expression of CD44 and Oct[4] is associated with poor survival.[7,8] the involvement of DAXX in regulating the expression of CD44 and Oct[4] has not been reported. A recent study showed that DAXX suppresses lung cancer metastasis by inhibiting EMT.[9] The role of DAXX in EMT in other types of cancers, including gastric cancer, remains unknown. We showed for the first time that DAXX inhibits the development of gastric cancer by inhibiting SNAI3- mediated EMT. We further showed that knockdown of DAXX in gastric cancer cells sustains cell survival, enhances the expression of stem cell markers CD44 and Oct[4] and promotes tumour growth
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