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.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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DNA Methylation / genetics
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Dioxygenases / genetics
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Dioxygenases / metabolism
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Down-Regulation / genetics
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mixed Function Oxygenases
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Neoplasm Invasiveness
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Tissue Inhibitor of Metalloproteinase-2 / biosynthesis*
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / biosynthesis*
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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DNA, Neoplasm
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DNA-Binding Proteins
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Proto-Oncogene Proteins
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TIMP2 protein, human
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TIMP3 protein, human
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Tissue Inhibitor of Metalloproteinase-3
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Tumor Suppressor Proteins
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Tissue Inhibitor of Metalloproteinase-2
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Mixed Function Oxygenases
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TET1 protein, human
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Dioxygenases