Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT

Harikrishna Nakshatri, H. N. Appaiah, M. Anjanappa, D. Gilley, Hiromi Tanaka, Sunil Badve, P. A. Crooks, W. Mathews, C. Sweeney, P. Bhat-Nakshatri

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The transcription factor nuclear factor-kappaB (Nf-kB) 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-kB 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-kB-dependent and -independent manner. DMAPT-mediated Nf-kB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of Nf-kB 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-kB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive Nf-kB activity. Overexpression of a constitutively active p65 subunit of Nf-kB 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-kB inhibition. These results add KMT5C to the list Nf-kB-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-kB-dependent and -independent cancer-specific epigenetic abnormalities.

Original languageEnglish (US)
Article numbere1608
JournalCell Death and Disease
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Epigenomics
Neoplasms
Histone Deacetylase 1
Genomic Instability
Methyltransferases
Histones
Transcription Factors
Gene Expression
Water
DNA

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. / Nakshatri, Harikrishna; Appaiah, H. N.; Anjanappa, M.; Gilley, D.; Tanaka, Hiromi; Badve, Sunil; Crooks, P. A.; Mathews, W.; Sweeney, C.; Bhat-Nakshatri, P.

In: Cell Death and Disease, Vol. 6, No. 1, e1608, 01.01.2015.

Research output: Contribution to journalArticle

Nakshatri, H, Appaiah, HN, Anjanappa, M, Gilley, D, Tanaka, H, Badve, S, Crooks, PA, Mathews, W, Sweeney, C & Bhat-Nakshatri, P 2015, 'Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT', Cell Death and Disease, vol. 6, no. 1, e1608. https://doi.org/10.1038/cddis.2014.569
Nakshatri, Harikrishna ; Appaiah, H. N. ; Anjanappa, M. ; Gilley, D. ; Tanaka, Hiromi ; Badve, Sunil ; Crooks, P. A. ; Mathews, W. ; Sweeney, C. ; Bhat-Nakshatri, P. / Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. In: Cell Death and Disease. 2015 ; Vol. 6, No. 1.
@article{105d4461977e4658a0922588620a3cb1,
title = "Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT",
abstract = "The transcription factor nuclear factor-kappaB (Nf-kB) 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-kB 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-kB-dependent and -independent manner. DMAPT-mediated Nf-kB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of Nf-kB 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-kB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive Nf-kB activity. Overexpression of a constitutively active p65 subunit of Nf-kB 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-kB inhibition. These results add KMT5C to the list Nf-kB-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-kB-dependent and -independent cancer-specific epigenetic abnormalities.",
author = "Harikrishna Nakshatri and Appaiah, {H. N.} and M. Anjanappa and D. Gilley and Hiromi Tanaka and Sunil Badve and Crooks, {P. A.} and W. Mathews and C. Sweeney and P. Bhat-Nakshatri",
year = "2015",
month = "1",
day = "1",
doi = "10.1038/cddis.2014.569",
language = "English (US)",
volume = "6",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Nf-kB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT

AU - Nakshatri, Harikrishna

AU - Appaiah, H. N.

AU - Anjanappa, M.

AU - Gilley, D.

AU - Tanaka, Hiromi

AU - Badve, Sunil

AU - Crooks, P. A.

AU - Mathews, W.

AU - Sweeney, C.

AU - Bhat-Nakshatri, P.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - The transcription factor nuclear factor-kappaB (Nf-kB) 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-kB 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-kB-dependent and -independent manner. DMAPT-mediated Nf-kB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of Nf-kB 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-kB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive Nf-kB activity. Overexpression of a constitutively active p65 subunit of Nf-kB 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-kB inhibition. These results add KMT5C to the list Nf-kB-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-kB-dependent and -independent cancer-specific epigenetic abnormalities.

AB - The transcription factor nuclear factor-kappaB (Nf-kB) 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-kB 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-kB-dependent and -independent manner. DMAPT-mediated Nf-kB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of Nf-kB 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-kB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive Nf-kB activity. Overexpression of a constitutively active p65 subunit of Nf-kB 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-kB inhibition. These results add KMT5C to the list Nf-kB-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-kB-dependent and -independent cancer-specific epigenetic abnormalities.

UR - http://www.scopus.com/inward/record.url?scp=84927628424&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927628424&partnerID=8YFLogxK

U2 - 10.1038/cddis.2014.569

DO - 10.1038/cddis.2014.569

M3 - Article

C2 - 25611383

AN - SCOPUS:84927628424

VL - 6

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 1

M1 - e1608

ER -