Functions of TET Proteins in Hematopoietic Transformation

DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abno...

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Main Authors:	Han, Jae-A, An, Jungeun, Ko, Myunggon
Format:	Online
Language:	English
Published:	Korean Society for Molecular and Cellular Biology 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673406/

id	pubmed-4673406
recordtype	oai_dc
spelling	pubmed-46734062015-12-11 Functions of TET Proteins in Hematopoietic Transformation Han, Jae-A An, Jungeun Ko, Myunggon Minireview DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents. Korean Society for Molecular and Cellular Biology 2015-11-30 2015-11-10 /pmc/articles/PMC4673406/ /pubmed/26552488 http://dx.doi.org/10.14348/molcells.2015.0294 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Han, Jae-A An, Jungeun Ko, Myunggon
spellingShingle	Han, Jae-A An, Jungeun Ko, Myunggon Functions of TET Proteins in Hematopoietic Transformation
author_facet	Han, Jae-A An, Jungeun Ko, Myunggon
author_sort	Han, Jae-A
title	Functions of TET Proteins in Hematopoietic Transformation
title_short	Functions of TET Proteins in Hematopoietic Transformation
title_full	Functions of TET Proteins in Hematopoietic Transformation
title_fullStr	Functions of TET Proteins in Hematopoietic Transformation
title_full_unstemmed	Functions of TET Proteins in Hematopoietic Transformation
title_sort	functions of tet proteins in hematopoietic transformation
description	DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.
publisher	Korean Society for Molecular and Cellular Biology
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673406/
_version_	1613510976040075264

Functions of TET Proteins in Hematopoietic Transformation

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