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Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors

Nature Genetics volume 33, pages 197–202 (2003)Cite this article

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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Figure 1: Phenotypes of Hic1+/− mice.
Figure 2: Analysis of malignant tumors for loss of heterozygosity.
Figure 3: Analysis of Hic1 promoter methylation in mouse tumors and tissues.
Figure 4: Bisulfite genomic sequencing and allele-specific methylation analysis of Hic1 promoters.
Figure 5: Immunohistochemical assessment of Hic1 expression.

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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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Authors and Affiliations

  1. Division of Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, 21231, Maryland, USA

    Wen Yong Chen, Xiaobei Zeng, Ray-Whay Chiu Yen, D. Neil Watkins, James G. Herman & Stephen B. Baylin

  2. Laboratory of Genetics, Developmental Genomics and Aging Section, National Institute on Aging, Baltimore, Maryland, USA

    Mark G. Carter

  3. Division of Comparative Medicine and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Craig N. Morrell & Joseph L. Mankowski

  4. Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain

    Manel Esteller

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  1. Wen Yong Chen
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Correspondence to Stephen B. Baylin.

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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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