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.
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.
|Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B (2014) Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest 124:56-63|
|Easwaran, Hariharan; Tsai, Hsing-Chen; Baylin, Stephen B (2014) Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 54:716-27|
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|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|
|Baylin, Stephen B (2012) The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications. Proc Am Thorac Soc 9:64-5|
|Clements, Eriko G; Mohammad, Helai P; Leadem, Benjamin R et al. (2012) DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res 40:4334-46|
|Easwaran, Hariharan; Johnstone, Sarah E; Van Neste, Leander et al. (2012) A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res 22:837-49|
|O'Hagan, Heather M; Wang, Wei; Sen, Subhojit et al. (2011) Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20:606-19|
|Mohammad, H P; Zhang, W; Prevas, H S et al. (2011) Loss of a single Hic1 allele accelerates polyp formation in Apc(?716) mice. Oncogene 30:2659-69|
|Yi, Joo Mi; Dhir, Mashaal; Van Neste, Leander et al. (2011) Genomic and epigenomic integration identifies a prognostic signature in colon cancer. Clin Cancer Res 17:1535-45|
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