Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers
Publication in refereed journal


摘要Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis.
著者Li LL, Li C, Mao HT, Du ZF, Chan WY, Murray P, Luo B, Chan ATC, Mok TSK, Chan FKL, Ambinder RF, Tao Q
期刊名稱Scientific Reports
詳細描述The Erratum to this article has been published in Scientific Reports 2016 6:34435 - "This Article contains errors in Figure 2D where the Hodgkin lymphoma ‘TET1-MSP’ methylated and unmethylated MSP bands are incorrect. The correct Figure 2D appears below as Figure 1."
Web of Science 學科類別Multidisciplinary Sciences; Science & Technology - Other Topics

上次更新時間 2020-25-11 於 02:13