TET1 Suppresses Cancer Invasion by Activating the Tissue Inhibitors of Metalloproteinases

Chih-Hung Hsu, Kai-Lin Peng, Ming-Lun Kang, Yi-Ren Chen, Yu-Chih Yang, Chin-Hsien Tsai, Chi-Shen Chu, Yung-Ming Jeng, Yen-Ting Chen, Feng-Mao Lin, Hsien-Da Huang, Yun-Yuh Lu, Yu-Ching Teng, Shinn-Tsuen Lin, Ruo Kai Lin, Fan-Mei Tang, Sung-Bau Lee, Huan-Ming Hsu, Jyh-Cherng Yu, Pei-Wen HsiaoLi-Jung Juan

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Abstract

Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation

Original languageEnglish
Pages (from-to)568-579
Number of pages12
JournalCell Reports
Volume2
Issue number3
DOIs
Publication statusPublished - Sep 27 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hsu, C-H., Peng, K-L., Kang, M-L., Chen, Y-R., Yang, Y-C., Tsai, C-H., Chu, C-S., Jeng, Y-M., Chen, Y-T., Lin, F-M., Huang, H-D., Lu, Y-Y., Teng, Y-C., Lin, S-T., Lin, R. K., Tang, F-M., Lee, S-B., Hsu, H-M., Yu, J-C., ... Juan, L-J. (2012). TET1 Suppresses Cancer Invasion by Activating the Tissue Inhibitors of Metalloproteinases. Cell Reports, 2(3), 568-579. https://doi.org/10.1016/j.celrep.2012.08.030