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.
We 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.
DAXX 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.
We for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.
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Ethics approval and consent to participate
All experiments involving human subjects were performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki), and the relevant guidelines and regulations of Soochow University. All experimental protocols were approved by the Research Ethics Committee of the First Affiliated Hospital of Soochow University. With informed consents from all subjects, paired specimens of GC and adjacent normal tissues were collected from patients who underwent surgical resection. None of the patients received anticancer therapy before surgery. Animal experiments complied with the ARRIVE guidelines, and were carried out in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).
All pertinent data to support this study are included in the paper and supplementary files. Further data supporting the findings are available upon request.
The authors declare no competing interests.
This work was supported by The National Natural Science Foundation of China (NSFC, Nos. 81871952, 81670358 and 81873528), Six talent peaks project in Jiangsu Province (BU24600117), the project for the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and National Center for International Research (2017B01012).
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Wu, C., Ding, H., Wang, S. et al. DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0800-3