Loss of a single Hic1 allele accelerates polyp formation in Apc Δ716 mice

H. P. Mohammad, W. Zhang, H. S. Prevas, B. R. Leadem, M. Zhang, J. G. Herman, C. M. Hooker, D. N. Watkins, B. Karim, D. L. Huso, S. B. Baylin

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Adenomatous polyposis coli (APC) gene mutations have been implicated in familial and sporadic gastrointestinal (GI) cancers. APC mutations are associated with autosomal dominant inheritance of disease in humans. Similarly, mice that contain a single mutant APC gene encoding a protein truncated at residue 716 (ApcΔ716) develop multiple polyps throughout the GI tract as early as 4 weeks after birth. Inactivation of another tumor suppressor gene, Hypermethylated in Cancer 1 (HIC1), often occurs in human colon cancers, among others, via CpG island hypermethylation. Homozygous deletion of Hic1 in mice results in major developmental defects and embryonic lethality. Hic1 heterozygotes have previously been shown to develop tumors of a variety of tissue types. We now report that loss of a single Hic1 allele can promote crypt hyperplasia and neoplasia of the GI tract, and Hic1+/-, Apc +/Δ716 double heterozygotes (DH) develop increased numbers of polyps throughout the GI tract at 60 days. Hic1 expression is absent in polyps from DH mice, with concomitant increased expression of two transcriptional repression targets of Hic1, Sirt1 and Sox9. Together, our data suggest that loss of a gene frequently silenced via epigenetic mechanisms, Hic1, can cooperate with loss of a gene mutated in GI cancer, Apc, to promote tumorigenesis in an in vivo model of multiple intestinal neoplasia.

Original languageEnglish (US)
Pages (from-to)2659-2669
Number of pages11
JournalOncogene
Volume30
Issue number23
DOIs
StatePublished - Jun 9 2011

Keywords

  • DNA hypermethylation
  • Hic1
  • Min
  • Polyp
  • colon cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Mohammad, H. P., Zhang, W., Prevas, H. S., Leadem, B. R., Zhang, M., Herman, J. G., Hooker, C. M., Watkins, D. N., Karim, B., Huso, D. L., & Baylin, S. B. (2011). Loss of a single Hic1 allele accelerates polyp formation in Apc Δ716 mice. Oncogene, 30(23), 2659-2669. https://doi.org/10.1038/onc.2010.633