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Death domain-associated protein (DAXX) is a complex biological multifunctional protein and is involved in the tumorigenesis and progression of multiple cancers. The accumulation of DAXX in the nucleus is a common phenomenon in tumor cells. However, altering the subcellular localizations of DAXX results in different biological functions, and we also found that its nuclear/cytoplasmic ratio (NCR) was associated with poor prognosis in gastric cancer (GC). In this study, we investigated the effect of cytoplasmic and nuclear DAXX (cDAXX and nDAXX) in GC and the underlying mechanisms. Immunohistochemical detection performed in 323 GC tissues reveled that cDAXX was associated with a better survival, while high nDAXX expression suggested a poorer prognosis outcome. Upregulation of DAXX in the cytoplasm inhibited cell proliferation and promoted apoptosis, whereas downregulation of DAXX in the nucleus displayed opposite effects. Moreover, Transwell assays revealed that DAXX enhanced GC cell migration and invasion. Analysis from the Gene Expression Profile Interactive Analysis (GEPIA) database showed that the expression of DAXX was significantly associated with SUMO-2/3 in GC tissues. Co-immunoprecipitation combined with immunofluorescence analysis indicated that DAXX interacted directly with SUMO-2/3. Subsequently, down-regulating the expression of SUMO-2/3 resulted in altered subcellular localization of DAXX. Bioinformatics analysis showed that RanBP2 may act as SUMO E3 ligase to promote nuclear-plasma transport via combining with RanGAP1. Taken together, our results indicated that DAXX plays opposing roles in GC and suggest a new model whereby cDAXX, nDAXX, and SUMO-2/3 form a molecular network that regulates the subcellular localization of DAXX and thereby modulates its opposing biological effects. Thus, our findings provide a foundation for future studies of DAXX as a novel therapeutic target for patients with GC.

Opposing biological functions of the cytoplasm and nucleus DAXX modified by SUMO-2/3 in gastric cancer