c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells

The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report t...

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Main Authors: Lim, Jun Feng, Grumont, Raelene, Gerondakis, Steve, Su, I-hsin, Neo, Wen Hao
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2015
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Online Access:https://hdl.handle.net/10356/79473
http://hdl.handle.net/10220/25127
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-794732023-02-28T16:58:21Z c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells Lim, Jun Feng Grumont, Raelene Gerondakis, Steve Su, I-hsin Neo, Wen Hao School of Biological Sciences DRNTU::Science::Biological sciences::Biochemistry The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report that c-Rel is a critical activator of Ezh2 transcription in lymphoid cells. In activated primary murine B and T cells, plus human leukemia and multiple myeloma cell lines, recruitment of c-Rel to the first intron of the Ezh2 locus promoted Ezh2 mRNA expression. This up-regulation was abolished in activated c-Rel-deficient lymphocytes and by c-Rel knockdown in Jurkat T cells. Treatment of malignant cells with the c-Rel inhibitor pentoxifylline not only reduced c-Rel nuclear translocation and Ezh2 expression, but also enhanced their sensitivity to the Ezh2-specific drug, GSK126 through increased growth inhibition and cell death. In summary, our demonstration that c-Rel regulates Ezh2 expression in lymphocytes and malignant lymphoid cells reveals a novel transcriptional network in transformed lymphoid cells expressing high levels of Ezh2 that provides a molecular justification for combinatorial drug therapy. Accepted version 2015-02-27T01:22:17Z 2019-12-06T13:26:11Z 2015-02-27T01:22:17Z 2019-12-06T13:26:11Z 2014 2014 Journal Article Neo, W. H., Lim, J. F., Grumont, R., Gerondakis, S., & Su, I.-h. (2014). c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. Journal of biological chemistry, 289(46), 31693-31707. https://hdl.handle.net/10356/79473 http://hdl.handle.net/10220/25127 10.1074/jbc.M114.574517 25266721 en Journal of biological chemistry © 2014 American Society for Biochemistry and Molecular Biology. This is the author created version of a work that has been peer reviewed and accepted for publication by The Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [Article URL/DOI: http://dx.doi.org/10.1074/jbc.M114.574517]. 26 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Biochemistry
spellingShingle DRNTU::Science::Biological sciences::Biochemistry
Lim, Jun Feng
Grumont, Raelene
Gerondakis, Steve
Su, I-hsin
Neo, Wen Hao
c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
description The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report that c-Rel is a critical activator of Ezh2 transcription in lymphoid cells. In activated primary murine B and T cells, plus human leukemia and multiple myeloma cell lines, recruitment of c-Rel to the first intron of the Ezh2 locus promoted Ezh2 mRNA expression. This up-regulation was abolished in activated c-Rel-deficient lymphocytes and by c-Rel knockdown in Jurkat T cells. Treatment of malignant cells with the c-Rel inhibitor pentoxifylline not only reduced c-Rel nuclear translocation and Ezh2 expression, but also enhanced their sensitivity to the Ezh2-specific drug, GSK126 through increased growth inhibition and cell death. In summary, our demonstration that c-Rel regulates Ezh2 expression in lymphocytes and malignant lymphoid cells reveals a novel transcriptional network in transformed lymphoid cells expressing high levels of Ezh2 that provides a molecular justification for combinatorial drug therapy.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Lim, Jun Feng
Grumont, Raelene
Gerondakis, Steve
Su, I-hsin
Neo, Wen Hao
format Article
author Lim, Jun Feng
Grumont, Raelene
Gerondakis, Steve
Su, I-hsin
Neo, Wen Hao
author_sort Lim, Jun Feng
title c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
title_short c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
title_full c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
title_fullStr c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
title_full_unstemmed c-rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells
title_sort c-rel regulates ezh2 expression in activated lymphocytes and malignant lymphoid cells
publishDate 2015
url https://hdl.handle.net/10356/79473
http://hdl.handle.net/10220/25127
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