This long standing RO1 explores epigenetic abnormalities underlying the initiation and progression of colorectal cancer (CRC), the third most common cause of cancer deaths in the US (U.S. Cancer Statistics Working Group). We are now defining novel perspectives for CRC evolution concerning the presence and position of epigenetic changes, key causes for how they arise and are maintained, and a new understanding of the functional significance of the transcriptional abnormalities for the genes affected. During the last funding cycle, we have integrally linked all of the above with environmental stresses underlying the earliest steps in CRC tumorigenesis. These tie resulting epigenetic abnormalities to the highest CRC risk states, chronic inflammation and especially aging. The above epigenetic dynamics intersect with, and may be obligatory for key genetic alterations to drive the evolution of CRC. An integrating molecular paradigm for all of the above concerns our defining, during the present funding cycle, a novel potential role for recruiting components of the NURD transcriptional repression complex to chromatin as triggered by reactive oxygen species (ROS) exposure and resultant DNA damage . Experimentally, this can associate with initiation and maintenance of abnormal gene expression associated with enhancer and gene promoter DNA methylation. In this proposal, we make novel use of colon organoids to model how the above DNA damage dynamics can underlie epigenetic abnormalities, which allow addiction to key genetic driver mutations to foster colon CRC risk including that associated with aging. Finally, we utilize the molecular events in the above risk paradigm for defining novel targets for reversing abnormal epigenetic gene silencing during CRC initiation and progression. Our proposed studies are then important for derivation of new strategies for prevention, interception, and therapy for CRC. All of the work in our proposal has the potential to define strategies for CRC prevention, interception and therapy underpinned by a novel relationship of the emerging data to the age-risk for these cancers.
We will investigate, in colorectal cancer (CRC) cells, assembly for key components of the NURD transcription complex which we have found can trigger, during reactive oxygen species induced DNA damage in CRC, initiation and maintenance of functional epigenetic abnormalities. We have tied the downstream repressed genes involved to the age-related risk of CRC in humans and have a model for this in organoids from colon. We will explore, including in our above model and with respect to key new proteins including PARP, UHRF1 and TET2, the hierarchy of complex assembly with a translational goal of targeting key members for new strategies to prevent, intersect, and manage CRC.
|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|
|Zhang, Yang W; Wang, Zhihong; Xie, Wenbing et al. (2017) Acetylation Enhances TET2 Function in Protecting against Abnormal DNA Methylation during Oxidative Stress. Mol Cell 65:323-335|
|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|
|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|
|Ahuja, Nita; Sharma, Anup R; Baylin, Stephen B (2016) Epigenetic Therapeutics: A New Weapon in the War Against Cancer. Annu Rev Med 67:73-89|
|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|
|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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