Abstract
Background
Colorectal cancer (CRC) is one of the most common malignant tumors with high recurrence and mortality. Thymine DNA glycosylase (TDG) is one of the key molecules involved in base excision repair pathway. Recently, more and more attentions have been paid to the role of TDG on tumor development. However, the specific functions of TDG in CRC remain unclear.
Methods
The biological functions of TDG and DNA methyltransferase 3 alpha (DNMT3A) in CRC were evaluated using migration and invasion assay. Tumor metastasis assay was performed in nude mice to detect the role of TDG in vivo. The interaction of TDG with DNMT3A was determined by co-immunoprecipitation (Co-IP). Chromatin immunoprecipitation analysis (CHIP) was applied to predict the DNA binding site of DNMT3A. We also performed methylation-specific PCR (MSP) to detect the changes in TIMP2 methylation levels.
Results
We found that TDG could inhibit the migration and invasion of human colon cancer cells in vitro and in vivo. TDG promoted the ubiquitination and degradation of DNMT3A by binding with it. Interference with siDNMT3A also inhibited the migration and invasion of human colon cancer cells. Further ChIP, MSP, and rescue experiments data confirmed that TDG accelerated the degradation of DNMT3A, and then significantly regulated the transcription and expression of TIMP2, thereby affecting the migration and invasion of human colon cancer cells.
Conclusion
Our findings reveal that TDG inhibit the migration and invasion of human colon cancer cells through DNMT3A-TIMP2 axis which may be potential therapeutic strategies in the development and treatment of CRC.
In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells
