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theses

Cancer chemoprevention is defined as the strategy to block or slow the onset of premalignant tumors and using relatively nontoxic chemical substance. Recently, accumulating experimental evidence has suggested that epigenetic alterations are involved in cancer development. The scope of epigenetics lies on the molecular interface between genetics and environmental factors; external factors switch genes on and off by influencing how cells read the genes. DNA methylation, histone covalent modification and remodeling, miRNA-mediated gene silencing represent the major mechanisms that play important role in epigenetic control of gene expression. This thesis focused on elucidating the epigenetic mechanisms in cancer prevention by dietary phytochemicals. Nrf2 is a master regulator of the antioxidant response and xenobiotic metabolism through the regulation of a wide range of antioxidant and phase II detoxification genes. The cellular protective role of Nrf2 points its potential as a primary target in chemoprevetion. Our group has reported that within tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model, there is a progressive loss of expression of Nrf2 and its downstream target genes, which is associated CpG hypermethylation in the promoter region. Using TRAMP C1 cells, we demonstrated that sulforaphane is a potent demethylation agent and it restores the epigenetically silenced Nrf2 gene through DNA demethylation. JB6 cells are derived from normal skin epidermis. We found that hypermethylation of Nrf2 promoter also exists in the transformation sensitive JB6 P+ cell line. The epigenetic reactivation of the Nrf2 signaling pathway by Tanshinone IIA could potentially contribute to the attenuation of JB6 P+ cellular transformation under the challenge of TPA, a tumor promoter. On the other hand, histone modification, in particular acetylation of H3K27 residue, is implicated in the transcription activation of pro-survival, pro-proliferative, and pro-inflammatory genes following TPA treatment. Bromodomain and extraterminal domain (BET) proteins function as epigenetic reader that recognizes acetylated histone tails and recruits the transcription machinery. Our study revealed that a small molecule BET inhibitor JQ-1 exerts potent anti-cancer and anti-inflammatory effects by interfering with the core transcriptional program of neoplastic transformation. Last but not least, altered levels of miRNA have been linked to tumor malignancy due to their ability to regulate functional gene expression in carcinogenesis. Using oligonucleotide microarray approach we identified the most affected miRNAs in LNCaP cells. Then we further assessed one potential target of PEITC - miR-194 in prostate cancer cell invasiveness. Collectively, dietary phytochemicals could modulate cellular epigenetic events that in part contribute to the cancer preventive effects. Given that oxidative stress and inflammation reaction are important (micro) environmental factors in malignancy transformation, understanding the role of redox and inflammatory signaling in epigenetic regulation could bring novel insights in cancer prevention.

ETD_7808

Ph.D.

Includes bibliographical references

by Chengyue Zhang

doi:10.7282/T3N01903

ETD doctoral

The author owns the copyright to this work.