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

114 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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    Chen, W. Y., Cooper, T., Zahnow, C. A., Overholtzer, M., Zhao, Z., Ladanyi, M., Karp, J. E., Gokgoz, N., Wunder, J. S., Andrulis, I. L., Levine, A. J., Mankowski, J. L., & 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