Epigenetic regulation plays a critical role for both the stable maintenance of cellular identity and the reprogramming process. Accumulating evidence suggests that epigenetic abnormalities represented by abnormal DNA methylation have been involved in cancer development. Taking advantage of reprogramming technology to actively alter epigenetic regulation, we are investigating the role of epigenetic regulation on cancer development, maintenance, and progression. Finally, we will try to develop a novel approach targeting epigenetic regulation to treat cancer patients.
Research and Education
Although cancer is generally believed to develop through accumulation of multiple genetic mutations, there is increasing evidence that cancer cells also acquire epigenetic abnormalities during development, maintenance, and progression. Because the epigenetic status of somatic cells changes dynamically through reprogramming, iPS cell technology can be utilized to actively and globally alter the epigenetic status of differentiated cells. Using this technology, we recently have proposed that some types of cancer can develop mainly through disruption of the epigenetic status triggered by dedifferentiation. We are also trying to reprogram cancer cells to uncover the role of epigenetic regulation in cancer cells. The data obtained would be applicable for devising novel strategies for both prevention and treatment of cancer.
Figure 1:Premature termination of in vivo reprogramming results in cancer development in the kidney. Lgr5-EGFP allele was used to visualize the failed reprogramming-associated kidney tumor cells. (Left panel)
Reduced representation bisulfite sequencing (RRBS) analysis revealed partial reorganization of DNA methylation pattern in failed reprogramming-associated cancers. (right panel)
1.Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, Soejima H, Moriwaki H, Yamanaka S, Woltjen K, Yamada Y. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 156: 663-77, 2014.
2.Yamada K,Ohno T, Aoki H, Semi K, Watanabe A, Moritake H, Shiozawa S, Kunisada T, Kobayashi Y, Toguchida J, Shimizu K, Hara A and Yamada Y*. EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice. Journal of Clinical Investigation, 123: 600-10, 2013.
3.Hirata A, Utikal J, Yamashita S, Aoki H, Watanabe A, Yamamoto T, Okano H, Bardeesy N, Kunisada T, Ushijima T, Hara A, Jaenisch R, Hochedlinger K*, Yamada Y*. Dose-dependent roles for canonical Wnt signaling in de novo crypt formation and cell cycle properties of the colonic epithelium. Development, 140: 66-75, 2013.
4.Aoki H., Hara A., Era T., Kunisada T., Yamada Y*. Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis. Development, 2012 Feb;139(4):667-77.
5.Yamada Y*, Aoki H, Kunisada T and Hara A. Rest promotes the early differentiation of mouse ESCs but is not required for their maintenance. Cell Stem Cell, 6: 10-15, 2010.
Immunology and Cell Biology
Professor Yasuhiro Yamada
Researcher Katsunori Semi