Project 3 studies food components as histone deacetylase (HDAC) inhibitors. HDAC inhibitors 'de-repress'epigenetically silenced genes, such as P21/WAF1, through Sp1/Sp3 transcription factor binding sites in the corresponding gene promoters, causing growth arrest/apoptosis in cancer cells. The PI has championed the view that dietary HDAC inhibitors might act similarly in the therapeutic setting, but because of their ingestion in foods they also serve a chemopreventive role via epigenetic 'priming'of gene expression in normal cells. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (I3C), and the cruciferous vegetables from which they derive, are effective chemopreventive agents in the colon because, in addition to their blocking activities during the initiation phase, they inhibit HDAC activity and alter the pattern of histone modifications (acetylation, methylation, phosphorylation) in cancer cells, thereby de-repressing epigenetically silenced genes such as P21 that regulate the cell cycle and apoptosis.
Aims 1 -3 start with mechanistic studies in human colon cancer cells, followed by preclinical dose-response experiments in a rat colon cancer model, ending with human translational work (colonoscopy screening).
Aim 1. In human colon cancer cells treated with SFN and I3C, define the changes HDACs, histone status (acetylation/methylation/phosphorylation), and Sp1/Sp3 transcription factor binding on the promoter region of P21, and mechanisms of HDAC inhibition. Study the DNA methylation status of the P21 promoter and changes in non-histone targets such as p53.
This aim uses immunoblotting, ChlP/re-ChIP, co-IP and qRT-PCR to examine reversible histone modifications, p21 de-repression, and HDAC inhibition/turnover.
Aim 2. In the 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) rat colon carcinogenesis model, examine chemoprevention of colon cancer using whole foods (broccoli sprouts, Brussels sprouts) and individual phytochemicals (SFN, I3C), Validate epigenetic biomarkers from Aim 1 as predictors of colon tumor outcome. Integrate with Projects 1 and 2 by examining other tissues (lung, thymus, prostate) for epigenetic biomarkers that might be applied in the clinical setting, such as during colonoscopy screening.
Aim 3. In patients presenting for screening colonoscopy, recruit low, mid, and high cruciferous vegetable consumers and assess tissue biopsy specimens and circulating blood cells for HDAC activity and histone status. Measure SFN metabolites as a biomarker of cruciferous vegetable intake, using LC/MS/MS in the Epigenetic/Translational Biomarkers core, and the mutation status of K-ras in colon biopsies.
In addition to genetic changes affecting DNA sequence information, we now realize that cancer development involves so-called epigenetic events, which represent a major new research priority area at NIH. One aspect of intense current interest concerns the histone (protein) modifications that silence tumor suppressor genes in cancer cells. We find that dietary agents can reverse such modifications, thereby re-expressing tumor suppressor genes and triggering cancer cells to arrest their growth and/or commit suicide via apoptosis.
|Madeen, Erin P; Williams, David E (2017) Environmental PAH exposure and male idiopathic infertility: a review on early life exposures and adult diagnosis. Rev Environ Health 32:73-81|
|Beaver, Laura M; Kuintzle, Rachael; Buchanan, Alex et al. (2017) Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer. J Nutr Biochem 42:72-83|
|Palomera-Sanchez, Zoraya; Watson, Gregory W; Wong, Carmen P et al. (2017) The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells. J Nutr Biochem 47:113-119|
|Chen, Ying-Shiuan; Wang, Rong; Dashwood, Wan-Mohaiza et al. (2017) A miRNA signature for an environmental heterocyclic amine defined by a multi-organ carcinogenicity bioassay in the rat. Arch Toxicol 91:3415-3425|
|Wang, Rong; Chen, Ying-Shiuan; Dashwood, Wan-Mohaiza et al. (2017) Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors. Mol Carcinog 56:1733-1742|
|Madeen, Erin P; Löhr, Christiane V; You, Hannah et al. (2017) Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice. Mol Carcinog 56:163-171|
|Johnson, Gavin S; Li, Jia; Beaver, Laura M et al. (2017) A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res 61:|
|Ertem, Furkan U; Zhang, Wenqian; Chang, Kyle et al. (2017) Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam. Int J Cancer 140:460-468|
|Kim, Hyemee; Banerjee, Nivedita; Barnes, Ryan C et al. (2017) Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo. Mol Carcinog 56:197-207|
|Wang, Rong; Kang, Yuki; Löhr, Christiane V et al. (2016) Reciprocal regulation of BMF and BIRC5 (Survivin) linked to Eomes overexpression in colorectal cancer. Cancer Lett 381:341-8|
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