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Int J Biol Sci 2022; 18(6):2527-2539. doi:10.7150/ijbs.69266 This issue Cite

Research Paper

TDG suppresses the migration and invasion of human colon cancer cells via the DNMT3A/TIMP2 axis

Jiyu Miao^1,2*, Changan Zhao^3,4*, Kaijie Tang¹, Xiaofan Xiong⁵, Fei Wu⁶, Wanjuan Xue⁷, Baojun Duan⁸, Huahua Zhang⁹, Xintao Jing¹, Wen Li¹, Ying Sun³, Ni Hou^1,4,10✉, Chen Huang^1,4,10,11✉

1. Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
2. Department of Hematology, The Second Affiliated Hospital of Xian Jiaotong University, Xi'an 710004, China.
3. Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
4. Institute of Genetics and Developmental Biology, Xi'an Jiaotong University, Xi'an 710061, China.
5. National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xian Jiaotong University, Xi'an 710004, China.
6. Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
7. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of oral biology, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
8. Department of Medical Oncology of Shaanxi Provincial People's Hospital, Xi'an 710068, China.
9. Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an 716000, China.
10. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an 710061, China.
11. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Xi'an 710004, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Ni Hou, E-mail: houniedu.cn; Chen Huang, E-mail: hchenedu.cn; Tel/fax: +86 29 8265 5077.

Abstract

Background: Colorectal cancer (CRC) is one of the most common malignant tumors with high rates of recurrence and mortality. Thymine DNA glycosylase (TDG) is a key molecule in the base excision repair pathway. Recently, increasing attention has been paid to the role of TDG in 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 assays, respectively. A tumor metastasis assay was performed in nude mice to determine the in vivo role of TDG. The interaction between TDG and DNMT3A was determined via co-immunoprecipitation (Co-IP). Chromatin immunoprecipitation analysis (ChIP) was used to predict the DNA-binding site of DNMT3A. We also performed methylation-specific PCR (MSP) to detect changes in TIMP2 methylation.

Results: TDG inhibited the migration and invasion of human colon cancer cells both in vitro and in vivo. TDG promoted the ubiquitination and degradation of DNMT3A by binding to it. Its interference with siDNMT3A also inhibits the migration and invasion of human colon cancer cells. Furthermore, the ChIP, MSP, and rescue experiments results confirmed that TDG accelerated the degradation of DNMT3A and 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 inhibits the migration and invasion of human colon cancer cells through the DNMT3A-TIMP2 axis, which may be a potential therapeutic strategy for the development and treatment of CRC.

Keywords: Colorectal cancer, TDG, DNMT3A, TIMP2, metastases, methylation

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