Received: 25 June 2018 | Accepted: 17 August 2018 DOI: 10.1002/jcp.27359 ORIGINAL RESEARCH ARTICLE Tet methylcytosine dioxygenase 1 promotes hypoxic gene induction and cell migration in colon cancer Ling Ma 1 | Tianyang Qi 2 | Shensen Wang 1 | Miao Hao 2 | Ali Sakhawat 1 | Tianya Liang 1 | Lin Zhang 1 | Xianling Cong 2 | Yinghui Huang 1 1 Cancer Institute, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China 2 Tissue Bank, China‐Japan Union Hospital, Jilin University, Changchun, China Correspondence Xianling Cong, China‐Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun 130033, China. Email: congxl@jlu.edu.cn Yinghui Huang, College of Life Science and Bioengineering, Beijing University of Technology, 100 Pingleyuan, Beijing 100124, China. Email: yhuang@bjut.edu.cn Funding information National Natural Science Foundation of China, Grant/Award Number: 81472209; Key Programs of Beijing Municipal Science & Technology Commission, Grant/Award Number: K2015311201501 Abstract Ten‐eleven translocation 1 (TET1), a widely reported DNA demethylation protein, has been associated with tumorigenesis and metastasis. However, whether TET1 is an oncogene or tumor suppressor gene has been controversial; the mechanism of how TET1 affects cancer progression remains unclear. The current study aims to investigate how TET1 is changed in the tumor microenvironment and to explore the mechanisms of how TET1 affects colon cancer progression. Because hypoxia prevails on solid tumors, we established an important connection between hypoxia and DNA demethylation in tumorigenesis. By qPCR and RNA interference (RNAi) technology, we found that hypoxia increased TET1 expression with a hypoxia‐ inducible factor‐1‐alpha (HIF‐1α)‐dependent manner. By CHIP‐qPCR and pyrose- quencing technology, we demonstrated that TET1 regulated the target gene expression of HIF‐1α through HIF‐1α binding to hypoxia‐responsive elements (HREs), and HIF‐1α binding to HREs depended on CpG methylation levels. By Cell Counting Kit-8 (CCK-8) and transwell assay, we showed that loss of TET1 did not affect cell proliferation but inhibited migration. We also identified two novel gene mutants of TET1 in 120 paired tumor/normal tissue specimens by DNA sequencing and found that TET1 E2082K mutant blocked the TET1‐enhanced cell migration. Our results showed that the downregulation of TET1 rescued the abnormally high levels of gene expression resulting from hypoxia in tumors and reduced the migration activity of tumor cells, suggesting a therapeutic role by interference with TET1 in colon cancer treatment. By demonstrating that hypoxia upregulated TET1 and that TET1 drove HIF‐1α‐responsive genes, we showed that an epigenetic mechanism and tumor microenvironment‐driven models coexisted and mutually affected colon cancer. KEYWORDS colon cancer, hypoxia, hypoxia‐inducible factor‐1 (HIF‐1), mutation, ten‐eleven translocation 1 (TET1) protein 1 | INTRODUCTION Epigenetics, including DNA methylation and histone modification, plays an essential role in numerous cellular processes by altering gene expression (Dawson & Kouzarides, 2012). Many types of epigenetic changes can be observed in different stages of carcinogenesis (Baylin & Jones, 2011), among which DNA methylation is one of the most important events (Li, 2002). In general, CpG hypermethylation of the gene promoter leads to tumor suppressor gene silencing by recruiting methylation binding proteins and preventing access to transcription J Cell Physiol. 2018;1–12. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1