This long standing RO1 explores epigenetic abnormalities underlying the evolution of colorectal cancer (CRC). We have defined the presence and significance of the many genes that evolve promoter, CpG island, DNA hypermethylation, and associated gene silencing in CRC. During the present funding cycle, we have integrally linked these above events with environmental stresses underlying the earliest steps in CRC tumorigenesis. In this competitive renewal, we take this paradigm forward by tying epigenetic events to the CRC risk state of chronic inflammation, and how it interacts with key genetic alterations to drive the evolution of CRC, the third most common cause of cancer deaths in the US (U.S. Cancer Statistics Working Group). Specifically, we have observed that exposure to reactive oxygen species (ROS) can rapidly induce the targeting, to CpG rich gene promoter regions, of protein complexes which can initiate gene promoter, DNA hypermethylation. These complexes contain not only DNA methyltransferases (DNMT's), the enzymes which catalyze DNA methylation, but also other transcriptional repression proteins which key candidates for initiating, and maintaining, DNA hypermethylation and attendant gene silencing. Among the proteins involved are the polycomb silencing group (PcG) and SIRT1, both players in DNA damage responses, and from our recent data, the NURD complex, transcriptionally repressive chromatin remodeling complex. Finally, we show in a mouse knockout model how HIC-1, a gene which is not mutated, but frequently epigenetically silenced in human CRC, can help drive early events in colon tumorigenesis. We have defined how loss of function of this gene, which encodes a transcriptional repression factor important in development, causes key stem compartment alterations in the intestine, and includes among its repression targets,SIRT1. We now explore further, using in-vivo and in-vitro models, how the protein complexes above initiate and maintain inflammation induced gene silencing, including for HIC1, and how these epigenetic abnormalities work with genetic alterations to foster CRC risk/initiation. The studies in this proposal provide insights for understanding how environmental risk factors underlie CRC risk/initiation and define molecular steps which are candidate targets for preventing CRC.

Public Health Relevance

A common event in the early risk/initiation stages of colorectal cancer (CRC) is abnormal, promoter, CpG island, DNA hypermethylation and associated epigenetic gene silencing. We investigate the molecular mechanisms though which this arises and how it fosters CRC risk and initiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011858-26
Application #
9279133
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Tyson, Frederick L
Project Start
1991-04-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
26
Fiscal Year
2017
Total Cost
$438,207
Indirect Cost
$167,709
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Cai, Yi; Tsai, Hsing-Chen; Yen, Ray-Whay Chiu et al. (2017) Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells. Genome Res 27:533-544
Xia, Limin; Huang, Wenjie; Bellani, Marina et al. (2017) CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes. Cancer Cell 31:653-668.e7
Vaz, Michelle; Hwang, Stephen Y; Kagiampakis, Ioannis et al. (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell 32:360-376.e6
Ding, Ning; Bonham, Emily M; Hannon, Brooke E et al. (2016) Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. J Mol Cell Biol 8:244-54
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Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B (2014) Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest 124:56-63
Cai, Y; Geutjes, E-J; de Lint, K et al. (2014) The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes. Oncogene 33:2157-68
Cui, Ying; Hausheer, Frederick; Beaty, Robert et al. (2014) A recombinant reporter system for monitoring reactivation of an endogenously DNA hypermethylated gene. Cancer Res 74:3834-43

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