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 mm(3) in WT mice and from 14.6 to 11.7 mm(3) 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.
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
authors.forename: Wan-Mohaiza
authors.initials: WM
authors.lastname: Dashwood
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
authors.forename: Eunah
authors.initials: E
authors.lastname: Kim
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Johnson
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, OR USA.
authors.forename: Kay A
authors.initials: KA
authors.lastname: Fischer
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, OR USA.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR USA ; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR USA ; College of Public Health and Human Sciences, Oregon State University, Corvallis, OR USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Ho
authors.affiliation: Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Medicine, Oregon Health & Science University, Portland, OR USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lieberman
authors.affiliation: Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA ; Department of Food Science & Nutrition, Texas A&M University, College Station, TX USA ; Department of Molecular & Cellular Medicine, Texas A&M University, College Station, TX USA ; Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX USA.
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Dashwood
keywords: Broccoli; Colon cancer; HDAC3; Nrf2; Sulforaphane; p16