HINT2 downregulation promotes colorectal carcinoma migration and metastasis

// Weihua Li 1, * , Shaoxin Cai 1, * , Le Wang 1 , Changshun Yang 1 , Biaohuan Zhou 1 , Huan Wang 1 1 Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China * These authors contributed equally to this work Correspondence to: Weihua Li, email: liwh68@sina.com Keywords: colorectal cancer, HINT2, epithelial–mesenchymal transition, HIF-2α, ZEB1 Received: June 30, 2016 Accepted: January 03, 2017 Published: January 10, 2017 ABSTRACT Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2'-deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter. HINT2 downregulation increased tumor migration and invasion in vitro , promoted CRC cell metastasis in vivo , and increased expression of epithelial-to-mesenchymal transition (EMT) markers. Furthermore, HINT2 downregulation depended on hypoxia inducible factor (HIF)-2α-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2α expression, which induces EMT and enhances CRC cell migration and invasion. HINT2 may thus a useful clinical indicator of CRC progression and metastasis risk.