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

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Clinical Epigenetics

, 7:102

First Online: 18 September 2015Received: 30 June 2015Accepted: 02 September 2015


BackgroundThe 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.

ResultsWild 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 mm in WT mice and from 14.6 to 11.7 mm 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.

ConclusionsNrf2 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.

KeywordsHDAC3 p16 Nrf2 Colon cancer Sulforaphane Broccoli AbbreviationsAcH4K12acetyl histone H4 lysine 12

ACTBhuman β-actin gene

Actbmurine β-actin gene

Apcadenomatous polyposis coli-multiple intestinal neoplasia

BSEbroccoli sprout extract

Cdkn1a-p21cyclin-dependant kinase inhibitor 1A

Cdkn2a-p16cyclin-dependant kinase inhibitor 2A

Cdkn2b-p15cyclin-dependent kinase inhibitor 2B

ChIPchromatin immunoprecipitation

CVFFQcruciferous vegetable food frequency questionnaire

Cyp2E1cytochrome P450 isoform 2E1


EDTAethylene diamine tetraacetic acid

Esr1estrogen receptor 1

Ets1E26 avian leukemia oncogene 1,5′ domain

HDAChistone deacetylase

HDAC1histone deacetylase 1

HDAC3histone deacetylase 3

HO1heme oxygenase-1

Igf2rinsulin-like growth factor 2 receptor

Keap1Kelch-like ECH-associated protein 1

MetMet proto-oncogene

MGMTO-alkylguanine DNA methyltransferase

Mlh1mutL homolog 1

Nrf2nuclear factor erythroid 2 NF-E2-related factor 2

OISoncogene-induced senescence

Tp53transformation-related protein 53

PBMCsperipheral blood mononuclear cells

ppmparts per million

Prkcaprotein kinase C, alpha

Runx1runt-related transcription factor 1

Serpin b5serine peptidase inhibitor






TCGAThe Cancer Genome Atlas

WTwild type

Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0132-y contains supplementary material, which is available to authorized users.

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Autor: Praveen Rajendran - Wan-Mohaiza Dashwood - Li Li - Yuki Kang - Eunah Kim - Gavin Johnson - Kay A. Fischer - Christiane V.


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