USP22 drives colorectal cancer invasion and metastasis via epithelial-mesenchymal transition by activating AP4

Abstract

// Yongmin Li 1, * , Yanmei Yang 2, * , Jingwen Li 1, * , He Liu 1 , Fuxun Chen 2 , Bingyang Li 2 , Binbin Cui 1 , Yanlong Liu 1 1 Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, China 2 Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, China * These authors contributed equally to this work Correspondence to: Binbin cui, email: cuibinbin222@hotmail.com Yanlong Liu, email: liuyanlong1979@163.com Keywords: USP22, liver metastasis, colorectal cancer, EMT, AP4 Received: October 12, 2016      Accepted: February 22, 2017      Published: March 06, 2017 ABSTRACT Ubiquitin specific peptidase 22 (USP22), a putative cancer stem cell marker, is overexpressed in liver metastases of colorectal cancer (CRC). However, the mechanism by which USP22 promotes CRC metastasis remains largely unknown. Here, we report that USP22 and AP4 are simultaneously overexpressed during TGF-β1-induced CRC cell epithelial-mesenchymal transition (EMT). USP22 up-regulation enhances CRC cell migration and invasion and EMT-related marker and AP4 expression, but these effects are partly blocked by AP4 knockdown. In addition, USP22 binds to the promoter region of AP4 to activate its transcription. In vivo , elevated USP22 expression promotes CRC cell metastasis to the lungs in nude mice, as evidenced by the fact that CRC metastatic nodules stain deeply positive for USP22 and AP4. In human CRC tissues, the genes encoding USP22 and AP4 are overexpressed in metastatic liver lesions compared with primary cancer tissues, and their overexpression is significantly associated with poor CRC patient survival. These findings indicate that USP22 and AP4 may serve as prognostic markers for predicting the risk of developing distant metastases in CRC.