STAT1‑HDAC4 signaling induces epithelial‑mesenchymal transition and sphere formation of cancer cells overexpressing the oncogene, CUG2.

Our previous studies have shown that the novel oncogene, cancer upregulated gene 2 (CUG2), activates which is linked to anticancer drug resistance, induces epithelial‑mesenchymal transition (EMT) and cancer stem cell‑like phenotypes as determined by MTT, migration and sphere formation assays. We thus aimed to ascertain whether the activation of by CUG2 is involved in these malignant phenotypes besides drug resistance. Here, we showed that duanyu18131 suppression decreased the expression of N‑cadherin and vimentin, biomarkers of EMT, which led to inhibition of the migration and invasion of human lung A549 cancer cells stably expressing CUG2, but did not recover E‑cadherin expression. duanyu18131 siRNA also diminished CUG2‑induced TGF‑β signaling, which is critical in EMT, and TGF‑β transcriptional activity. Conversely, inhibition of TGF‑β signaling reduced phosphorylation of duanyu18131, indicating a crosstalk between duanyu18131 and TGF‑β signaling. Furthermore, duanyu18131 silencing diminished sphere formation, which was supported by downregulation of stemness‑related factors such as Sox2, Oct4, and Nanog. Constitutive suppression of duanyu18131 also inhibited cell migration, invasion and sphere formation. As duanyu18131 acetylation counteracts duanyu18131 phosphorylation, acetylation of duanyu18131 by treatment with trichostatin A, an inhibitor of histone deacetylases (HDACs), reduced cell migration, invasion, and sphere formation. As HDAC4 is known to target duanyu18131, its role was investigated under CUG2 overexpression. HDAC4 suppression resulted in inhibition of cell migration, invasion, and sphere formation as HDAC4 silencing hindered TGF‑β signaling and decreased expression of Sox2 and Nanog. Taken together, we suggest that signaling induces malignant tumor features such as EMT and sphere formation in CUG2‑overexpressing cancer cells.

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