Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon

Praveen Rajendran, Wan Mohaiza Dashwood, Li Li, Yuki Kang, Eunah Kim, Gavin Johnson, Kay A. Fischer, Christiane V. Löhr, David E. Williams, Emily Ho, Masayuki Yamamoto, David Lieberman, Roderick H. Dashwood

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies. Results: Wild type (WT) and Nrf2-deficient (Nrf2−/+) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2−/+ mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm3 in WT mice and from 14.6 to 11.7 mm3 in Nrf2−/+ mice. The decreased antitumor activity of SFN in Nrf2−/+ mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy. Conclusions: Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.

Original languageEnglish (US)
Article number102
JournalClinical Epigenetics
Volume7
Issue number1
DOIs
StatePublished - Sep 18 2015

Fingerprint

NF-E2-Related Factor 2
Colon
Histone Deacetylases
Growth
Genes
Neoplasms
Colonic Neoplasms
1,2-Dimethylhydrazine
Cyclins
Histone Deacetylase Inhibitors
sulforafan
Brassica
Large Intestine
Hematologic Neoplasms
Colonoscopy
Tumor Burden
Vegetables
Carcinogens
Blood Cells
Phosphotransferases

Keywords

  • Broccoli
  • Colon cancer
  • HDAC3
  • Nrf2
  • p16
  • Sulforaphane

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Developmental Biology
  • Genetics(clinical)

Cite this

Rajendran, P., Dashwood, W. M., Li, L., Kang, Y., Kim, E., Johnson, G., ... Dashwood, R. H. (2015). Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon. Clinical Epigenetics, 7(1), [102]. https://doi.org/10.1186/s13148-015-0132-y

Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon. / Rajendran, Praveen; Dashwood, Wan Mohaiza; Li, Li; Kang, Yuki; Kim, Eunah; Johnson, Gavin; Fischer, Kay A.; Löhr, Christiane V.; Williams, David E.; Ho, Emily; Yamamoto, Masayuki; Lieberman, David; Dashwood, Roderick H.

In: Clinical Epigenetics, Vol. 7, No. 1, 102, 18.09.2015.

Research output: Contribution to journalArticle

Rajendran, P, Dashwood, WM, Li, L, Kang, Y, Kim, E, Johnson, G, Fischer, KA, Löhr, CV, Williams, DE, Ho, E, Yamamoto, M, Lieberman, D & Dashwood, RH 2015, 'Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon', Clinical Epigenetics, vol. 7, no. 1, 102. https://doi.org/10.1186/s13148-015-0132-y
Rajendran, Praveen ; Dashwood, Wan Mohaiza ; Li, Li ; Kang, Yuki ; Kim, Eunah ; Johnson, Gavin ; Fischer, Kay A. ; Löhr, Christiane V. ; Williams, David E. ; Ho, Emily ; Yamamoto, Masayuki ; Lieberman, David ; Dashwood, Roderick H. / Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon. In: Clinical Epigenetics. 2015 ; Vol. 7, No. 1.
@article{cc61b30c984b4922aeba78e1a4322930,
title = "Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon",
abstract = "Background: The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies. Results: Wild type (WT) and Nrf2-deficient (Nrf2−/+) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2−/+ mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm3 in WT mice and from 14.6 to 11.7 mm3 in Nrf2−/+ mice. The decreased antitumor activity of SFN in Nrf2−/+ mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy. Conclusions: Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.",
keywords = "Broccoli, Colon cancer, HDAC3, Nrf2, p16, Sulforaphane",
author = "Praveen Rajendran and Dashwood, {Wan Mohaiza} and Li Li and Yuki Kang and Eunah Kim and Gavin Johnson and Fischer, {Kay A.} and L{\"o}hr, {Christiane V.} and Williams, {David E.} and Emily Ho and Masayuki Yamamoto and David Lieberman and Dashwood, {Roderick H.}",
year = "2015",
month = "9",
day = "18",
doi = "10.1186/s13148-015-0132-y",
language = "English (US)",
volume = "7",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon

AU - Rajendran, Praveen

AU - Dashwood, Wan Mohaiza

AU - Li, Li

AU - Kang, Yuki

AU - Kim, Eunah

AU - Johnson, Gavin

AU - Fischer, Kay A.

AU - Löhr, Christiane V.

AU - Williams, David E.

AU - Ho, Emily

AU - Yamamoto, Masayuki

AU - Lieberman, David

AU - Dashwood, Roderick H.

PY - 2015/9/18

Y1 - 2015/9/18

N2 - Background: The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies. Results: Wild type (WT) and Nrf2-deficient (Nrf2−/+) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2−/+ mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm3 in WT mice and from 14.6 to 11.7 mm3 in Nrf2−/+ mice. The decreased antitumor activity of SFN in Nrf2−/+ mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy. Conclusions: Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.

AB - Background: The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies. Results: Wild type (WT) and Nrf2-deficient (Nrf2−/+) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2−/+ mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm3 in WT mice and from 14.6 to 11.7 mm3 in Nrf2−/+ mice. The decreased antitumor activity of SFN in Nrf2−/+ mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy. Conclusions: Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.

KW - Broccoli

KW - Colon cancer

KW - HDAC3

KW - Nrf2

KW - p16

KW - Sulforaphane

UR - http://www.scopus.com/inward/record.url?scp=84961215708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961215708&partnerID=8YFLogxK

U2 - 10.1186/s13148-015-0132-y

DO - 10.1186/s13148-015-0132-y

M3 - Article

AN - SCOPUS:84961215708

VL - 7

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

M1 - 102

ER -