Abstract
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.
Highlights
DNA methylation at the C5 position of cytosine (5-methylcytosine, 5-mC), known as the “fifth base”, is a key epigenetic modification at CpG dinucleotides, playing critical roles in normal development and disease pathogenesis including tumorigenesis[1]
The newly identified 5-hydroxymethylcytosine (5 hmC) in mammalian genomic DNA6, as an intermediate of active DNA demethylation, has been recognized as the “sixth base”, which provides us new insight into the regulation of CpG methylation dynamics via active demethylation. 5 hmC is readily expressed in human normal tissues and embryonic stem cells, but becomes greatly decreased in multiple cancer tissues[7,8,9]
Inactive mutations or deletions of TET2 with impaired catalytic activity were frequently detected in hematopoietic malignancies[14], along with decreased 5 hmC levels[4,15,16], while no somatic TET1 or TET3 mutation was found in myeloid and lymphoid tumors
Summary
CpG demethylase TET1 as a DNA methylation feedback loop in received: 15 January 2016 accepted: 05 May 2016 Published: 26 May 2016 human cancers. 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. 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. DNA methylation at the C5 position of cytosine (5-methylcytosine, 5-mC), known as the “fifth base”, is a key epigenetic modification at CpG dinucleotides, playing critical roles in normal development and disease pathogenesis including tumorigenesis[1]. Regional promoter CpG methylation together with genome-wide hypomethylation, as a fundamental epigenetic hallmark of cancers, lead to the silencing of tumor suppressor genes (TSG) and activation of oncogenes, contributing to cancer initiation and progression. We discovered frequent promoter methylation of TET1 in a large set of tumor cell lines and primary tumors, and confirmed its tumor suppressive functions and demethylation activity in tumor cells
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