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

Wen Yong Chen; Xiaobei Zeng; Mark G. Carter; Craig N. Morrell; Ray Whay Chiu Yen; Manel Esteller; D. Neil Watkins; James G. Herman; Joseph L. Mankowski; Stephen B. Baylin

doi:10.1038/ng1077

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

Wen Yong Chen, Xiaobei Zeng, Mark G. Carter, Craig N. Morrell, Ray Whay Chiu Yen, Manel Esteller, D. Neil Watkins, James G. Herman, Joseph L. Mankowski, Stephen B. Baylin

School of Medicine

Research output: Contribution to journal › Article › peer-review

183 Scopus citations

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 cancer^1,3-5. 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.

Original language	English (US)
Pages (from-to)	197-202
Number of pages	6
Journal	Nature genetics
Volume	33
Issue number	2
DOIs	https://doi.org/10.1038/ng1077
State	Published - Feb 1 2003

ASJC Scopus subject areas

Genetics

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title = "Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors",

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 cancer1,3-5. 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.",

author = "Chen, {Wen Yong} and Xiaobei Zeng and Carter, {Mark G.} and Morrell, {Craig N.} and {Chiu Yen}, {Ray Whay} and Manel Esteller and Watkins, {D. Neil} and Herman, {James G.} and Mankowski, {Joseph L.} and Baylin, {Stephen B.}",

note = "Funding Information: 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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doi = "10.1038/ng1077",

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AU - Chen, Wen Yong

AU - Zeng, Xiaobei

AU - Carter, Mark G.

AU - Morrell, Craig N.

AU - Chiu Yen, Ray Whay

AU - Esteller, Manel

AU - Watkins, D. Neil

AU - Herman, James G.

AU - Mankowski, Joseph L.

AU - Baylin, Stephen B.

N1 - Funding Information: 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.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - 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 cancer1,3-5. 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.

AB - 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 cancer1,3-5. 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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Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors

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