Loss of a single Hic1 allele accelerates polyp formation in ApcΔ716 mice
Open Access
- 7 February 2011
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 30 (23), 2659-2669
- https://doi.org/10.1038/onc.2010.633
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.Keywords
This publication has 45 references indexed in Scilit:
- SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signalingProceedings of the National Academy of Sciences of the United States of America, 2010
- A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1Oncogene, 2010
- A Prospective Cohort Study Shows Unique Epigenetic, Genetic, and Prognostic Features of Synchronous Colorectal CancersGastroenterology, 2009
- A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responsesNature Medicine, 2009
- Scavenger Chemokine (CXC Motif) Receptor 7 (CXCR7) Is a Direct Target Gene of HIC1 (Hypermethylated in Cancer 1)Journal of Biological Chemistry, 2009
- Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastomaGenes & Development, 2008
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007
- Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epitheliumThe Journal of cell biology, 2007
- HIC1 attenuates Wnt signaling by recruitment of TCF-4 and β-catenin to the nuclear bodiesThe EMBO Journal, 2006
- Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variablesThe Journal of Pathology, 1987