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Keywords {🔍}

hdac, colon, sfn, nrf, pubmed, expression, cancer, mice, fig, article, tumor, google, scholar, cas, tumors, human, gene, data, levels, histone, protein, dashwood, treatment, cells, central, genes, mouse, normal, additional, usa, sulforaphane, reported, dmh, diet, growth, deacetylase, cruciferous, bse, university, factor, subjects, metabolites, mrna, adjacent, inhibitor, cdknap, increased, normalized, βactin, study,

Topics {✒️}

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Questions {❓}

• Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?
• Epigenetic therapies move into new territory, but how exactly do they work?
• How good are rodent models of carcinogenesis in predicting efficacy in humans?
• Nrf2: friend or foe for chemoprevention?
• What, then, connects Nrf2 genetic background to altered HDAC3 levels on p16?

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         headline:Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon
         description: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. 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. 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.
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            address:
               name:Linus Pauling Institute, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
      name:Eunah Kim
      affiliation:
            name:Texas A&M Health Science Center
            address:
               name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Gavin Johnson
      affiliation:
            name:Texas A&M Health Science Center
            address:
               name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Kay A. Fischer
      affiliation:
            name:Oregon State University
            address:
               name:College of Veterinary Medicine, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
      name:Christiane V. Löhr
      affiliation:
            name:Oregon State University
            address:
               name:College of Veterinary Medicine, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
      name:David E. Williams
      affiliation:
            name:Oregon State University
            address:
               name:Linus Pauling Institute, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
            name:Oregon State University
            address:
               name:Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
      name:Emily Ho
      affiliation:
            name:Oregon State University
            address:
               name:Linus Pauling Institute, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
            name:Oregon State University
            address:
               name:College of Public Health and Human Sciences, Oregon State University, Corvallis, USA
               type:PostalAddress
            type:Organization
      name:Masayuki Yamamoto
      affiliation:
            name:Tohoku University Graduate School of Medicine
            address:
               name:Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
               type:PostalAddress
            type:Organization
      name:David A. Lieberman
      affiliation:
            name:Oregon Health & Science University
            address:
               name:Department of Medicine, Oregon Health & Science University, Portland, USA
               type:PostalAddress
            type:Organization
      name:Roderick H. Dashwood
      affiliation:
            name:Texas A&M Health Science Center
            address:
               name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
               type:PostalAddress
            type:Organization
            name:Texas A&M University
            address:
               name:Department of Food Science & Nutrition, Texas A&M University, College Station, USA
               type:PostalAddress
            type:Organization
            name:Texas A&M University
            address:
               name:Department of Molecular & Cellular Medicine, Texas A&M University, College Station, USA
               type:PostalAddress
            type:Organization
            name:MD Anderson Cancer Center
            address:
               name:Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:Linus Pauling Institute, Oregon State University, Corvallis, USA
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:College of Veterinary Medicine, Oregon State University, Corvallis, USA
      name:College of Veterinary Medicine, Oregon State University, Corvallis, USA
      name:Linus Pauling Institute, Oregon State University, Corvallis, USA
      name:Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, USA
      name:Linus Pauling Institute, Oregon State University, Corvallis, USA
      name:College of Public Health and Human Sciences, Oregon State University, Corvallis, USA
      name:Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
      name:Department of Medicine, Oregon Health & Science University, Portland, USA
      name:Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, USA
      name:Department of Food Science & Nutrition, Texas A&M University, College Station, USA
      name:Department of Molecular & Cellular Medicine, Texas A&M University, College Station, USA
      name:Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, USA

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