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
Johnson, Gavin S; Li, Jia; Beaver, Laura M et al. (2016) A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a co-activator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res :
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
Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng et al. (2016) HDAC6 activity is not required for basal autophagic flux in metastatic prostate cancer cells. Exp Biol Med (Maywood) 241:1177-85
Abbas, Ata; Hall, J Adam; Patterson 3rd, William L et al. (2016) Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines. Biochem Cell Biol 94:71-81
Ertem, Furkan; Dashwood, Wan-Mohaiza; Rajendran, Praveen et al. (2016) Development of a murine colonoscopic polypectomy model (with videos). Gastrointest Endosc 83:1272-6
Zhang, Zhenzhen; Atwell, Lauren L; Farris, Paige E et al. (2016) Associations between cruciferous vegetable intake and selected biomarkers among women scheduled for breast biopsies. Public Health Nutr 19:1288-95
Kim, Hyemee; Banerjee, Nivedita; Ivanov, Ivan et al. (2016) Comparison of anti-inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis. Mol Nutr Food Res 60:1912-23
Kim, Eunah; Bisson, William H; Löhr, Christiane V et al. (2016) Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors. Curr Top Med Chem 16:714-31
Harper Jr, Tod A; Morré, Jeff; Lauer, Fredine T et al. (2015) Analysis of dibenzo[def,p]chrysene-deoxyadenosine adducts in wild-type and cytochrome P450 1b1 knockout mice using stable-isotope dilution UHPLC-MS/MS. Mutat Res Genet Toxicol Environ Mutagen 782:51-6
Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng et al. (2015) Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells. Mol Nutr Food Res 59:1954-61

Showing the most recent 10 out of 111 publications