Abstract
Some feedback pathways are critical in the process of tumor development or malignant progression. However the mechanisms through which these pathways are epigenetically regulated have not been fully elucidated. Here, we demonstrated that the histone demethylase RBP2 was crucial for TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit that was implicated in malignant progression of tumors and its knockdown significantly inhibited gastric cancer (GC) metastasis both in vitro and in vivo. Mechanistically, RBP2 can directly bind to E-cadherin promoter and suppress its expression, facilitating EMT and distant metastasis of GC. RBP2 can also be induced by TGF-β1, a key inducer of EMT, through phosphorylated Smad3 (p-Smad3) pathway in GC. The upregulated RBP2 can be recruited by p-smad3 to E-cadherin promoter and enhance its suppression, contributing to the promotion of metastasis of GC. In addition, the suppression of E-cadherin by RBP2 attenuated inhibition of Smad3 phosphorylation (exerted by E-cadherin), resulting further induction of RBP2 expression, and thus constituting positive feedback regulation during GC malignant progression. This TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit may be a novel mechanism for GC malignant progression and suppression of RBP2 expression may serve as a new strategy for the prevention of tumor distant metastasis.
Highlights
gastric cancer (GC) malignant progression is the main reason for its poor prognosis, during which EMT is critical
We demonstrate that the TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit may be a novel mechanism for EMT and GC metastasis and targeting RBP2 expression may have therapeutic advantage for the prevention of tumor metastasis
Our group has evidenced the high expression of RBP2 in primary gastric cancer tissues, whether RBP2 expression correlated with tumor progression remained unclear
Summary
GC malignant progression is the main reason for its poor prognosis, during which EMT (epithelial-tomesenchymal transition) is critical. Characterized by downregulation of epithelial markers (e.g. E-cadherin and Occludin) and upregulation of mesenchymal markers (e.g. Vimentin, Snail-1, Slug, Twist and ZEB1), EMT enhances mobility of cancer cells, facilitating their distant metastasis [1,2,3]. The core event of EMT is the loss or inhibition of epithelial markers (such as E-cadherin) which causes damage to the conjunction between cells. Tumor cells often obtain the stem cell property during EMT which is the reason why it is sometimes easy www.impactjournals.com/oncotarget for cancer (including GC) to relapse [4]. It is urgent to unveil the underlying mechanism for EMT and this is instrumental in understanding the cause for tumor malignant progression
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