Epigenetics is a priority area in the NIH Roadmap. The Epigenetic/Translational Biomarkers (ETB) core has the overall goal of consolidating and applying standard methods to detect epigenetic modifications, for use in preclinical models and translational studies on Projects 1-3 of the P01. This core integrates with all three projects on the P01, with specific emphasis on methodologies and services that will be used most heavily and routinely throughout the 5-year course of investigation. This core evolved out of the prior """"""""Services Core"""""""" and retains several key elements, such as the histopathology and biostatistics components. However, it now incorporates several epigenetic assays of importance to the central hypothesis of the P01: The CENTRAL HYPOTHESIS is that sulforaphane (SFN), indole-3-carbinol (I3C), and cruciferous vegetables from which they derive are effective chemopreventive agents because, in addition to their blocking activities, they alter the pattern of histone modifications and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the ceil cycle and apoptosis. Based on the central hypothesis, the following broad specific aims will be implemented in the ETB core:
Aim 1. Provide histopathology expertise for preclinical studies in rats and mice (Projects 1-3), and immunohistochemical analyses of epigenetic biomarkers (acetylated histones, HDACs) in animal and human tissues. The latter analyses will include tissue microarrays from translational studies with prostate cancer patients and colonoscopy patients.
Aim 2. Conduct routine HDAC activity assays on tissues from preclinical and clinical studies (Projects 1-3).
Aim 3. Run DNA methylation assays for epigenetically silenced genes of mutual interest (Projects 1-3). Arm 4. Perform LC/MS/MS analyses of SFN and I3C metabolites in tissues and body fluids (Projects 1-3).
Aim 5. Coordinate protocol design and statistical analyses of data (Projects 1-3). The long-term goal is to better understand which assays and biomarker(s) for epigenetic alterations in cancers might be applied in a reliable and robust manner in the clinical setting.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA090890-10
Application #
8732427
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2014
Total Cost
$302,323
Indirect Cost
Name
Texas A&M University
Department
Type
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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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