PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407

• DOI: 10.1038/cddis.2017.111
• Publication Date: 2017-03-16T13:44:39Z
• Authors: Xin Tan; Shuai Chen; Jiangxue Wu; Jiaxin Lin; Changchuan Pan; Xiaofang Ying; Zhizhong Pan; Lin Qiu; Ranyi Liu; Rong Geng; Wenlin Huang
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; Intracellular Signaling Peptides and Proteins; Histone-Lysine N-Methyltransferase; HCT116 Cells; Prognosis; Cell Line; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; HEK293 Cells; Cell Movement; Cell Line, Tumor; Biomarkers, Tumor; Humans; Original Article; Neoplasm Metastasis; Colorectal Neoplasms; Promoter Regions, Genetic; HT29 Cells; Proto-Oncogene Proteins c-akt; Signal Transduction

AbstractColorectal cancer (CRC) is the third most common cause of cancer deaths, and has a high rate of liver and lung metastasis. Unfortunately, distant metastasis is the main barrier for advanced CRC therapy and leads to a very low survival rate. In this study, we identified WDR5, a vital factor that regulates vertebrate development and cell self-renewal and reprogramming, as a novel prognostic marker and therapeutic target for CRC patients. We demonstrate that WDR5 is upregulated in CRC tissues and promotes CRC metastasis both in vitro and in vivo. In an effort to investigate the impact of WDR5 on CRC cell fate, we treated CRC cells with growth factor and inhibitor. We report that WDR5 is a novel factor in the metastasis of CRC by triggering epithelial–mesenchymal transition (EMT) process in response to the PI3K/AKT signaling pathway. Moreover, WDR5 shows a direct binding to the ZNF407 promoter on regulating cellular EMT process, leading to CRC metastasis. Hence, our findings strongly position WDR5 as a valuable marker for CRC, and inhibiting WDR5 or the associated signaling pathways may be an effective strategy for the future development of anti-CRC therapy.