Histone demethylase RBP2 promotes malignant progression of gastric cancer through TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit

// Xiuming Liang 1 , Jiping Zeng 2 , Lixiang Wang 3 , Li Shen 1 , Xueping Ma 1 , Shuyan Li 1 , Yujiao Wu 1 , Lin Ma 1 , Xinyu Ci 1 , Qing Guo 6 , Mutian Jia 1 , Haiyu Shen 5 , Yundong Sun 1 , Zhifang Liu 2 , Shili Liu 1 , Wenjuan Li 1 , Han Yu 1 , Chunyan Chen 4 , Jihui Jia 1 1 Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China 2 Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China 3 Department of Pharmacology, School of Medicine, Shandong University, Jinan, PR China 4 Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, PR China 5 Department of Gastrointestinal Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong, PR China 6 Department of Nursing, Ningxia Peoples Hospital, Yinchuan, PR China Correspondence to: Jihui Jia, e-mail: jiajihui@sdu.edu.cn Keywords: RBP2, TGF-β1, feedback circuit, metastasis Received: November 30, 2014      Accepted: April 25, 2015      Published: May 07, 2015 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.