Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors.
The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor that belongs to a group of proteins known as the POZ family. HIC1 is hypermethylated and transcriptionally silent in several types of human cancer. Homozygous disruption of Hic1 impairs development and results in embryonic and perinatal lethality in mice. 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.
Chen
Wen Yong
WY
Division of Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, Maryland 21231, USA.
Zeng
Xiaobei
X
Carter
Mark G
MG
Morrell
Craig N
CN
Chiu Yen
Ray-Whay
RW
Esteller
Manel
M
Watkins
D Neil
DN
Herman
James G
JG
Mankowski
Joseph L
JL
Baylin
Stephen B
SB
D000818:Animals; D015139:Blotting, Southern; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011817:Rabbits; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012737:Sex Factors; D013447:Sulfites / Q000494:pharmacology; D013577:Syndrome; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C096870:Hic1 protein, mouse; D007074:Immunoglobulin G; D051741:Kruppel-Like Transcription Factors; D010446:Peptide Fragments; D013447:Sulfites; D014157:Transcription Factors; D012259:Ribonuclease, Pancreatic; C009279:sodium bisulfite