Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Cell Rep. 2012 Sep 27;2(3):568-79. doi: 10.1016/j.celrep.2012.08.030. Epub 2012 Sep 20.
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.
肿瘤抑制基因通过胞嘧啶甲基化失活导致癌症形成。是否有 DNA 去甲基化酶来对抗这种致癌作用尚不清楚。在这里，我们发现参与胞嘧啶去甲基化的双加氧酶 TET1 在前列腺癌和乳腺癌组织中下调。TET1 耗竭促进了前列腺异种移植模型中的细胞侵袭、肿瘤生长和癌症转移，并与乳腺癌患者的生存率降低相关。一致地，TET1 的强制表达减少了细胞侵袭和乳腺异种移植肿瘤的形成。在机制上，TET1 通过其双加氧酶和 DNA 结合活性抑制细胞侵袭。此外，TET1 通过抑制组织金属蛋白酶抑制剂 (TIMP) 家族蛋白 2 和 3 的 DNA 甲基化来维持其表达。在临床样本中，TET1 和 TIMP2 或 TIMP3 的同时低表达与晚期淋巴结状态相关。总之，这些结果说明了 TET1 通过下调关键基因的甲基化来抑制肿瘤发生和侵袭的部分机制。
