Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation

Kyung Chul Choi, Gu Jung Myung, Yoo Hyun Lee, Chun Yoon Joo, Hyun Kwon Seung, Hee Bum Kang, Mi Jeong Kim, JeongHeon Cha, Jun Kim Young, Jin Jun Woo, Myun Lee Jae, Ho Geun Yoon

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Abstract

Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-κB (NF-κB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 μmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α (TNFα)-induced NF-κB activation. We also showed that EGCG prevents TNFα-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-κB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-κB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-κB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 μmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.

Original languageEnglish
Pages (from-to)583-592
Number of pages10
JournalCancer Research
Volume69
Issue number2
DOIs
Publication statusPublished - 2009 Jan 15

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Histone Acetyltransferases
Acetylation
Lymphocyte Activation
Human Herpesvirus 4
B-Lymphocytes
Tumor Necrosis Factor-alpha
Epstein-Barr Virus Infections
Histone Deacetylases
Enzymes
Genetic Promoter Regions
Epigenomics
Genes
epigallocatechin gallate
Interleukin-6
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Choi, Kyung Chul ; Myung, Gu Jung ; Lee, Yoo Hyun ; Joo, Chun Yoon ; Seung, Hyun Kwon ; Kang, Hee Bum ; Kim, Mi Jeong ; Cha, JeongHeon ; Young, Jun Kim ; Woo, Jin Jun ; Jae, Myun Lee ; Yoon, Ho Geun. / Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. In: Cancer Research. 2009 ; Vol. 69, No. 2. pp. 583-592.
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title = "Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation",
abstract = "Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-κB (NF-κB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 μmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α (TNFα)-induced NF-κB activation. We also showed that EGCG prevents TNFα-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-κB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-κB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-κB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 μmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.",
author = "Choi, {Kyung Chul} and Myung, {Gu Jung} and Lee, {Yoo Hyun} and Joo, {Chun Yoon} and Seung, {Hyun Kwon} and Kang, {Hee Bum} and Kim, {Mi Jeong} and JeongHeon Cha and Young, {Jun Kim} and Woo, {Jin Jun} and Jae, {Myun Lee} and Yoon, {Ho Geun}",
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Choi, KC, Myung, GJ, Lee, YH, Joo, CY, Seung, HK, Kang, HB, Kim, MJ, Cha, J, Young, JK, Woo, JJ, Jae, ML & Yoon, HG 2009, 'Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation', Cancer Research, vol. 69, no. 2, pp. 583-592. https://doi.org/10.1158/0008-5472.CAN-08-2442

Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. / Choi, Kyung Chul; Myung, Gu Jung; Lee, Yoo Hyun; Joo, Chun Yoon; Seung, Hyun Kwon; Kang, Hee Bum; Kim, Mi Jeong; Cha, JeongHeon; Young, Jun Kim; Woo, Jin Jun; Jae, Myun Lee; Yoon, Ho Geun.

In: Cancer Research, Vol. 69, No. 2, 15.01.2009, p. 583-592.

Research output: Contribution to journalArticle

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T1 - Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation

AU - Choi, Kyung Chul

AU - Myung, Gu Jung

AU - Lee, Yoo Hyun

AU - Joo, Chun Yoon

AU - Seung, Hyun Kwon

AU - Kang, Hee Bum

AU - Kim, Mi Jeong

AU - Cha, JeongHeon

AU - Young, Jun Kim

AU - Woo, Jin Jun

AU - Jae, Myun Lee

AU - Yoon, Ho Geun

PY - 2009/1/15

Y1 - 2009/1/15

N2 - Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-κB (NF-κB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 μmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α (TNFα)-induced NF-κB activation. We also showed that EGCG prevents TNFα-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-κB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-κB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-κB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 μmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.

AB - Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-κB (NF-κB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 μmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α (TNFα)-induced NF-κB activation. We also showed that EGCG prevents TNFα-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-κB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-κB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-κB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 μmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.

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