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NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT

The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrat...

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Autores principales: Nakshatri, H, Appaiah, H N, Anjanappa, M, Gilley, D, Tanaka, H, Badve, S, Crooks, P A, Mathews, W, Sweeney, C, Bhat-Nakshatri, P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669767/
https://www.ncbi.nlm.nih.gov/pubmed/25611383
http://dx.doi.org/10.1038/cddis.2014.569
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author Nakshatri, H
Appaiah, H N
Anjanappa, M
Gilley, D
Tanaka, H
Badve, S
Crooks, P A
Mathews, W
Sweeney, C
Bhat-Nakshatri, P
author_facet Nakshatri, H
Appaiah, H N
Anjanappa, M
Gilley, D
Tanaka, H
Badve, S
Crooks, P A
Mathews, W
Sweeney, C
Bhat-Nakshatri, P
author_sort Nakshatri, H
collection PubMed
description The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities.
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spelling pubmed-46697672015-12-08 NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT Nakshatri, H Appaiah, H N Anjanappa, M Gilley, D Tanaka, H Badve, S Crooks, P A Mathews, W Sweeney, C Bhat-Nakshatri, P Cell Death Dis Original Article The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities. Nature Publishing Group 2015-01 2015-01-22 /pmc/articles/PMC4669767/ /pubmed/25611383 http://dx.doi.org/10.1038/cddis.2014.569 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Nakshatri, H
Appaiah, H N
Anjanappa, M
Gilley, D
Tanaka, H
Badve, S
Crooks, P A
Mathews, W
Sweeney, C
Bhat-Nakshatri, P
NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title_full NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title_fullStr NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title_full_unstemmed NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title_short NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT
title_sort nf-κb-dependent and -independent epigenetic modulation using the novel anti-cancer agent dmapt
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669767/
https://www.ncbi.nlm.nih.gov/pubmed/25611383
http://dx.doi.org/10.1038/cddis.2014.569
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