Abstract
The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor1 that belongs to a group of proteins known as the POZ family2. HIC1 is hypermethylated and transcriptionally silent in several types of human cancer1,3,4,5. Homozygous disruption of Hic1 impairs development and results in embryonic and perinatal lethality in mice6. Here we show that mice disrupted in the germ line for only one allele of Hic1 develop many different spontaneous malignant tumors, including a predominance of epithelial cancers in males and lymphomas and sarcomas in females. The complete loss of Hic1 function in the heterozygous mice seems to involve dense methylation of the promoter of the remaining wild-type allele. We conclude that HIC1 is a candidate tumor-suppressor gene for which loss of function in both mouse and human cancers is associated only with epigenetic modifications.
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Acknowledgements
We thank Y. Akiyama, O. Galm and B. Yang for discussion and suggestions; E. Garrett and S. Piantadosi for statistical advice; P. Wilcox for histology; and L. Meszler for microscopy. This study was supported by a grant from the US National Institutes of Health to S.B.B. C.N.M. was supported by a training grant from the US Public Health Service.
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J.G.H. and S.B.B. are consultants to Tibotec-Virco. Under licensing agreement between the Johns Hopkins University and Tibotec-Virco, M.S.P. was licensed to Tibotec-Virco and they are entitled to a share of the royalties received by the University from sales of the licensed technology. The terms of these arrangements are being managed by the University in accordance with its conflict of interests policies.
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Chen, W., Zeng, X., Carter, M. et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 33, 197–202 (2003). https://doi.org/10.1038/ng1077
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DOI: https://doi.org/10.1038/ng1077
