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Med Sci (Paris). 2006 Jan;22(1):54-61.

[Chromosome arm 17p13.3: could HIC1 be the one ?].

[Article in French]

Author information

  • 1ERI-8 Inserm, Signalisation des facteurs de croissance dans le cancer du sein, Protéomique fonctionnelle, UPRES EA 1033, IFR 118, Bâtiment SN3, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France. valerie.chopin@univ-lille1.fr

Abstract

Loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p) is one of the most frequent genetic alterations in human cancers. Most often, allelic losses coincide with p53 mutations at 17p13.1. However, in many types of solid tumors including sporadic breast cancers, ovarian cancers, medulloblastomas and small cell lung carcinomas, frequent LOH or DNA methylation changes occur in a more telomeric region at 17p13.3, in absence of any p53 genetic alterations. These results suggest that one or more tumor suppressor genes located at 17p13.3 could be involved in tumorigenesis. In addition, the 17p13.3 region has also been implicated in the Miller-Dieker syndrome (MDS), a severe form of lissencephaly accompanied by developmental anomalies caused by heterozygous gene deletions. Analyses of deletion mapping and CpG island methylation patterns have resulted in the identification of two tumor suppressor genes at 17p13.3, HIC1 (hypermethylated in cancer 1) and OVCA1 (ovarian cancer gene 1). HIC1 is a tumor suppressor gene that encodes a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and a N-terminal BTB/POZ domain. Clues to the tumor suppressor function of HIC1 have come from the study of heterozygous Hic1+/- mice, which develop spontaneous malignant tumors of different types. Generation of double heterozygous knockout mice Hic1+/- p53+/- provides strong evidence that epigenetically silenced genes such as HIC1 can significantly influence tumorigenesis driven by mutations of classic tumor suppressor genes. This functional cooperation between HIC1 and p53 is interesting and recently, its has been demonstrated that HIC1 was involved in a certain feedback regulation for p53 in tumor suppression through the histone deacetylase SIRT1. However, despite the fact that epigenetic oncogenesis is one of the most vibrant areas of biologic research, the determinants between genetic versus epigenetic routes of tumor suppressor gene inactivation remain elusive.

PMID:
16386221
[PubMed - indexed for MEDLINE]
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