Abstract
Ten-Eleven Translocation 1 (TET1) is a member of ten eleven translocation enzymes, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1 can promote CpG islands demethylation in specific genes and often absent in various cancers. Herein, we found that TET1 expression and 5-hmC content were low in gastric tumors compared to its adjacent non-tumor tissues. Cell proliferation, migration and invasion were enhanced upon TET1 knockdown in gastric cancer cells in vitro. This phenomenon was confirmed by an animal xeongraft model. We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands. TET1 knockdown activated AKT and FAK pathways, which were suppressed by PTEN. The activation of AKT and FAK facilitated tumor migration, invasion and accelerated cell growth. In conclusion, we found a novel mechanism that TET1 suppresses tumor cell growth, migration and invasion through demethylation of CpG island in PTEN promoter by increasing 5-hmC content. The re-expressed PTEN subsequently down regulates AKT and FAK activity.
Highlights
Ten eleven translocation enzymes (TET1, TET2 and TET3) are a family of dioxygenase, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and lead to CpG islands demethylation [1,2,3]. 5-hmC is regarded as “sixth base” and it is associated with active gene expression while 5-mC stands for gene silence [4]. 5-hmC is always enriched in the promoter region and its content is mainly depended on TET (TET1, TET2 and TET3) levels [5]
We found that Ten-Eleven Translocation 1 (TET1) mRNA was significantly reduced in gastric cancer tissues compared with the surrounding non-tumor tissues (p=0.036) (Figure 1A)
The Immunohistochemical staining (IHC) analysis showed that TET1 expression was reduced in 28 out of 35 gastric cancer samples compared to non-tumor tissues (Supplementary Figure S1)
Summary
Ten eleven translocation enzymes (TET1, TET2 and TET3) are a family of dioxygenase, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and lead to CpG islands demethylation [1,2,3]. 5-hmC is regarded as “sixth base” and it is associated with active gene expression while 5-mC stands for gene silence [4]. 5-hmC is always enriched in the promoter region and its content is mainly depended on TET (TET1, TET2 and TET3) levels [5]. DNA methylation and demethylation play essential roles in modulating chromosome structure and regulating specific gene expression or repression during cell differentiation. Gastric cancer is a kind of common cancers, and abnormal DNA methylation correlates with its initiation and progression, especially at the CpG islands located at promoter of tumor repressor genes [15]. TET1 as an epigenetic modulator plays an important role in inhibiting carcinogenesis by regulating 5-hmC and 5-mC content in www.impactjournals.com/oncotarget specific gene promoter. We revealed that over-expression of TET1 suppressed gastric cancer carcinogenesis through increasing 5-hmC and decreasing 5-mC content at promoter of tumor-suppressor gene PTEN. Our research work firstly clarified that TET1 up-regulates its target gene PTEN through increasing 5-hmC content of its promoter and eventually represses gastric cancer development
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