Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis

Wen Yong Chen, Timothy Cooper, Cynthia A. Zahnow, Michael Overholtzer, Zhiquan Zhao, Marc Ladanyi, Judith E. Karp, Nalan Gokgoz, Jay S. Wunder, Irene L. Andrulis, Arnold J. Levine, Joseph L. Mankowski, Stephen B. Baylin

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)387-398
Number of pages12
JournalCancer Cell
Volume6
Issue number4
DOIs
StatePublished - Oct 1 2004

Fingerprint

Epigenomics
Carcinogenesis
Osteosarcoma
Neoplasms
Genes
Chromosomes
Alleles
Gene Deletion
Tumor Suppressor Genes
Breast Neoplasms
Phenotype
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Chen, W. Y., Cooper, T., Zahnow, C. A., Overholtzer, M., Zhao, Z., Ladanyi, M., ... Baylin, S. B. (2004). Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell, 6(4), 387-398. https://doi.org/10.1016/j.ccr.2004.08.030
Chen, Wen Yong ; Cooper, Timothy ; Zahnow, Cynthia A. ; Overholtzer, Michael ; Zhao, Zhiquan ; Ladanyi, Marc ; Karp, Judith E. ; Gokgoz, Nalan ; Wunder, Jay S. ; Andrulis, Irene L. ; Levine, Arnold J. ; Mankowski, Joseph L. ; Baylin, Stephen B. / Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. In: Cancer Cell. 2004 ; Vol. 6, No. 4. pp. 387-398.
@article{316d186102f34a959ab5fc6493292a1b,
title = "Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis",
abstract = "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.",
author = "Chen, {Wen Yong} and Timothy Cooper and Zahnow, {Cynthia A.} and Michael Overholtzer and Zhiquan Zhao and Marc Ladanyi and Karp, {Judith E.} and Nalan Gokgoz and Wunder, {Jay S.} and Andrulis, {Irene L.} and Levine, {Arnold J.} and Mankowski, {Joseph L.} and Baylin, {Stephen B.}",
year = "2004",
month = "10",
day = "1",
doi = "10.1016/j.ccr.2004.08.030",
language = "English (US)",
volume = "6",
pages = "387--398",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",

}

Chen, WY, Cooper, T, Zahnow, CA, Overholtzer, M, Zhao, Z, Ladanyi, M, Karp, JE, Gokgoz, N, Wunder, JS, Andrulis, IL, Levine, AJ, Mankowski, JL & Baylin, SB 2004, 'Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis', Cancer Cell, vol. 6, no. 4, pp. 387-398. https://doi.org/10.1016/j.ccr.2004.08.030

Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. / Chen, Wen Yong; Cooper, Timothy; Zahnow, Cynthia A.; Overholtzer, Michael; Zhao, Zhiquan; Ladanyi, Marc; Karp, Judith E.; Gokgoz, Nalan; Wunder, Jay S.; Andrulis, Irene L.; Levine, Arnold J.; Mankowski, Joseph L.; Baylin, Stephen B.

In: Cancer Cell, Vol. 6, No. 4, 01.10.2004, p. 387-398.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis

AU - Chen, Wen Yong

AU - Cooper, Timothy

AU - Zahnow, Cynthia A.

AU - Overholtzer, Michael

AU - Zhao, Zhiquan

AU - Ladanyi, Marc

AU - Karp, Judith E.

AU - Gokgoz, Nalan

AU - Wunder, Jay S.

AU - Andrulis, Irene L.

AU - Levine, Arnold J.

AU - Mankowski, Joseph L.

AU - Baylin, Stephen B.

PY - 2004/10/1

Y1 - 2004/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=5444259434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=5444259434&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2004.08.030

DO - 10.1016/j.ccr.2004.08.030

M3 - Article

C2 - 15488761

AN - SCOPUS:5444259434

VL - 6

SP - 387

EP - 398

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 4

ER -

Chen WY, Cooper T, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell. 2004 Oct 1;6(4):387-398. https://doi.org/10.1016/j.ccr.2004.08.030