Mechanisms of tumor suppressor gene reactivation in colon cancer by berries

Summary

Principal Investigator: Li Shu Wang
Abstract: DESCRIPTION (provided by applicant): Although mortality rates from colorectal cancer have declined in both men and women over the past two decades, the 5-year survival from this disease is 64% and continues to decline to 57% at 10 years after diagnosis. For persons with distant metastases at diagnosis, the 5-year survival is only 10%. Therefore, the prevention of colon cancer remains an important goal and chemoprevention is a viable approach to achieve this goal. Our laboratory has been evaluating the use of freeze-dried berries, mainly black raspberries (BRBs), for the prevention of colon cancer in animals and in humans. The addition of BRB powder to the diet inhibited the development of colonic adenomas and carcinomas in azoxymethane (AOM)-treated rats, and of spontaneous adenomas in the intestine of ApcMin/+ mice. Two pilot intervention trials have been conducted in humans: one in patients with sporadic colorectal cancer and the other in patients with familial adenomatous polyposis (FAP). Our results suggest that short-term treatment of sporadic colorectal cancer patients with oral BRB powder (20g/3x/day) significantly reduced cell proliferation rates and produced a positive trend for changes in apoptosis, angiogenesis, and in genes associated with the Wnt pathway in colorectal tumors. Our FAP trial indicated that nine month treatment of FAP patients with BRB powder administered both orally (20g/3x/day) and in the form of rectal suppositories caused a 53% regression rate of rectal polyps. These results suggest that berries have potential for prevention of colorectal cancer in humans. Using bio-directed fractionation, we and our collaborators found that the anthocyanins in BRBs are important for their chemopreventive effects. Recent preliminary studies suggest that the colorectal cancer inhibitory effect of BRBs may be due, at least in part, to their ability to inhibit DNA methyltransferase 1 (DNMT1) protein expression and total DNMT activity in human colon tumor cells, which led to demethylation and reactivation of hypermethylation-silenced tumor suppressor genes such as p16. Short-term BRB intervention in colorectal cancer patients resulted in the demethylation of p16 and re-expression of the gene in aberrant crypts of colonic tumor tissues. We propose therefore to determine if demethylation and reactivation of hypermethylation- silenced genes by BRB anthocyanins in human colon cancer cells and in ApcMin/+ mice is associated with inhibition of tumorigenesis (Specific Aim 1) and the role of DNMT1 in BRB anthocyanin-induced demethylation of tumor suppressor genes (Specific Aim 2). We will also determine if BRBs influence the methylation state of hypermethylation-silenced tumor suppressor genes in specimens obtained from the two human BRB intervention trials, and its association with reduced cell proliferation and polyp regression (Specific Aim 3). Finally, we will conduct a pharmacokinetic study to determine the uptake of anthocyanins into human colon cells, and intestinal tissue and serum, as well as urinary levels of anthocyanins and their metabolites when administered at different concentrations in the diet to ApcMin/+ mice (Specific Aim 4). Ultimately, we plan to evaluate anthocyanins for prevention of colorectal cancer in humans. PUBLIC HEALTH RELEVANCE: Colon cancer is the third most prevalent cancer, and the third leading cause of cancer death in the United States. Our laboratory is developing strategies for the prevention of colon cancer using freeze-dried berries. We now propose to evaluate the anthocyanins in berries for their ability to demethylate and reactivate tumor suppressor genes in colon cancer.
Funding Period: 2010-04-08 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Profiling DNA methylomes from microarray to genome-scale sequencing
    Yi Wei Huang
    The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Technol Cancer Res Treat 9:139-47. 2010
  2. pmc An overview of epigenetics and chemoprevention
    Yi Wen Huang
    Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
    FEBS Lett 585:2129-36. 2011
  3. pmc Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: a phase I pilot study
    Li Shu Wang
    Department of Internal Medicine, Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio 43240, USA
    Clin Cancer Res 17:598-610. 2011
  4. pmc Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients
    Roycelynn A Mentor-Marcel
    Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute Frederick, Frederick, Maryland, USA
    Nutr Cancer 64:820-5. 2012
  5. pmc Black raspberry-derived anthocyanins demethylate tumor suppressor genes through the inhibition of DNMT1 and DNMT3B in colon cancer cells
    Li Shu Wang
    Medical College of Wisconsin, Division of Hematology and Oncology, Department of Medicine, Milwaukee, Wisconsin 53226, USA
    Nutr Cancer 65:118-25. 2013
  6. pmc Dietary black raspberries modulate DNA methylation in dextran sodium sulfate (DSS)-induced ulcerative colitis
    Li Shu Wang
    Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Carcinogenesis 34:2842-50. 2013
  7. pmc Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue
    Li Shu Wang
    Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, TBRC, Room C4930, Milwaukee, WI 53226
    Cancer Prev Res (Phila) 6:1317-27. 2013
  8. ncbi Chemoprevention of esophageal cancer with black raspberries, their component anthocyanins, and a major anthocyanin metabolite, protocatechuic acid
    Daniel S Peiffer
    Authors Affiliations Departments of Medicine, Pathology, and Obstetrics and Gynecology, Medical College of Wisconsin Cancer Center Agro BioSciences Inc, Milwaukee, Wisconsin and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    Cancer Prev Res (Phila) 7:574-84. 2014

Research Grants

Detail Information

Publications8

  1. pmc Profiling DNA methylomes from microarray to genome-scale sequencing
    Yi Wei Huang
    The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Technol Cancer Res Treat 9:139-47. 2010
    ..With advances on next-generation sequencing technologies, it is now possible to globally map the DNA cytosine methylation at single-base resolution, providing new insights into the regulation and dynamics of DNA methylation in genomes...
  2. pmc An overview of epigenetics and chemoprevention
    Yi Wen Huang
    Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
    FEBS Lett 585:2129-36. 2011
    ..Uncovering the human epigenome can lead us to better understand the dynamics of DNA methylation in disease progression which can further assist in cancer prevention...
  3. pmc Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: a phase I pilot study
    Li Shu Wang
    Department of Internal Medicine, Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio 43240, USA
    Clin Cancer Res 17:598-610. 2011
    ....
  4. pmc Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients
    Roycelynn A Mentor-Marcel
    Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute Frederick, Frederick, Maryland, USA
    Nutr Cancer 64:820-5. 2012
    ..52) observed in colorectal tissue taken within the same week. Plasma concentrations of GM-CSF and IL-8 may serve as noninvasive indicators to monitor tissue response to berry-based interventions for CRC...
  5. pmc Black raspberry-derived anthocyanins demethylate tumor suppressor genes through the inhibition of DNMT1 and DNMT3B in colon cancer cells
    Li Shu Wang
    Medical College of Wisconsin, Division of Hematology and Oncology, Department of Medicine, Milwaukee, Wisconsin 53226, USA
    Nutr Cancer 65:118-25. 2013
    ..In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers...
  6. pmc Dietary black raspberries modulate DNA methylation in dextran sodium sulfate (DSS)-induced ulcerative colitis
    Li Shu Wang
    Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Carcinogenesis 34:2842-50. 2013
    ..These results suggest that BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation...
  7. pmc Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue
    Li Shu Wang
    Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, TBRC, Room C4930, Milwaukee, WI 53226
    Cancer Prev Res (Phila) 6:1317-27. 2013
    ..In conclusion, our results suggest that BRBs inhibit colonic ulceration and, ultimately, colon cancer partly through inhibiting aberrant epigenetic events that dysregulate Wnt signaling...
  8. ncbi Chemoprevention of esophageal cancer with black raspberries, their component anthocyanins, and a major anthocyanin metabolite, protocatechuic acid
    Daniel S Peiffer
    Authors Affiliations Departments of Medicine, Pathology, and Obstetrics and Gynecology, Medical College of Wisconsin Cancer Center Agro BioSciences Inc, Milwaukee, Wisconsin and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    Cancer Prev Res (Phila) 7:574-84. 2014
    ..Overall, our data suggest that BRBs, their component ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis, at least in part, by their inhibitory effects on genes associated with inflammation...

Research Grants30

  1. Prevention of Esophageal Cancer with Berries
    Gary Stoner; Fiscal Year: 2013
    ..We now propose to evaluate the anthocyanins in berries in combination with phenethyl isothiocyanate in vegetables for their ability to prevent esophageal cancer at low, non-toxic, dietary concentrations. ..
  2. The Sphingolipid Pathway in Colon Cancer Chemoprevention
    Toshihiko Kawamori; Fiscal Year: 2013
    ..abstract_text> ..
  3. Colorectal Cancer Prevention Through Thyroid Hormone Targets
    ADAM ROBERT BROWN; Fiscal Year: 2013
    ..The successful completion of the study will provide insight into potential age-dependent targets that may lead to the development of new therapies to prevent or treat age-related colorectal cancer. ..