Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.
The gene hypermethylated in cancer 1 (HIC1) is epigenetically inactivated, but not mutated, in cancer. Here we show that cooperative loss of Hic1 with p53, but not INK4a, yields distinct tumor phenotypes in mice. Germline deletion of one allele of each gene on the opposite chromosome yields breast and ovarian carcinomas and metastatic osteosarcomas with epigenetic inactivation of the wild-type Hic1 allele. Germline deletion of the two genes on the same chromosome results in earlier appearance and increased prevalence and aggressiveness of osteosarcomas with genetic deletion of both wild-type genes. In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutations. Our results indicate the importance of genes altered only through epigenetic mechanisms in cancer progression in conjunction with genetically modified tumor suppressor genes.
Cancer Biology Program, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231, USA.
Wenyong
W
Chen
Timothy K
TK
Cooper
Cynthia A
CA
Zahnow
Michael
M
Overholtzer
Zhiquan
Z
Zhao
Marc
M
Ladanyi
Judith E
JE
Karp
Nalan
N
Gokgoz
Jay S
JS
Wunder
Irene L
IL
Andrulis
Arnold J
AJ
Levine
Joseph L
JL
Mankowski
Stephen B
SB
Baylin
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D002872:Chromosome Deletion; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53