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Originally published online as doi:10.2353/ajpath.2009.080148 on December 4, 2008

Published online before print December 4, 2008
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(American Journal of Pathology. 2009;174:309-316.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080148

Heterochromatin Protein 1{gamma} Epigenetically Regulates Cell Differentiation and Exhibits Potential as a Therapeutic Target for Various Types of Cancers

Masakatsu Takanashi*{dagger}, Kosuke Oikawa*{dagger}, Koji Fujita*, Motoshige Kudo*, Masao Kinoshita{ddagger} and Masahiko Kuroda*

From the Departments of Pathology,* and Cell Therapy,{dagger} Tokyo Medical University, Tokyo, Japan; and Department of Surgery,{ddagger} Kosei Chuo General Hospital

Heterochromatin protein 1 (HP1) is a chromosomal protein that participates in both chromatin packaging and gene silencing. Three HP1 isoforms ({alpha}, β, and {gamma}) occur in mammals, but their functional differences are still incompletely understood. In this study, we found that HP1{gamma} levels are decreased during adipocyte differentiation, whereas HP1{alpha} and β levels are expressed constitutively during adipogenesis in cultured preadipocyte cells. In addition, ectopic overexpression of HP1{gamma} inhibited adipogenesis. Furthermore, we did not detect any HP1{gamma} protein in the differentiated cells of various normal human tissues. These results suggest that the loss of HP1{gamma} is required for cell differentiation to occur. On the other hand, the methylation levels of lysine 20 (K20) on histone H4 showed a significant correlation with HP1{gamma} expression in both these preadipocyte cells and normal tissue samples. However, all cancer tissues examined were positive for HP1{gamma} but were often negative for trimethylated histone H4 K20. Thus, a dissociation of the correlation between HP1{gamma} expression and histone H4 K20 trimethylation may reflect the malfunction of epigenetic control. Finally, suppression of HP1{gamma} expression restrained cell growth in various cancer-derived cell lines, suggesting that HP1{gamma} may be an effective target for gene therapy against various human cancers. Taken together, our results demonstrate the novel function of HP1{gamma} in the epigenetic regulation of both cell differentiation and cancer development.






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