HIC1 : le nœud du problème en 17p13.3 ?

Abstract

Le bras court du chromosome 17 (17p) est fréquemment altéré dans les cancers humains, notamment au niveau du gène p53. Cependant, dans certains cancers, des altérations en 17p concernent des régions distales de p53, en l’absence de toute mutation de ce gène. Des analyses de perte d’hétérozygotie et de méthylation des îlots CpG présents dans les promoteurs de gènes ont permis d’identifier en 17p13.3 plusieurs nouveaux gènes suppresseurs de tumeur proches les uns des autres, tels que HIC1 (hypermethylated in cancer 1) et OVCA1 (ovarian cancer gene 1). HIC1 est d’autant plus intéressant que l’extinction de son expression est, jusqu’à présent, préférentiellement due à l’hyperméthylation de son promoteur, et qu’il a été récemment décrit l’existence d’une boucle de régulation entre HIC1 et p53. Toutefois, si l’impact des modifications épigénétiques dans la tumorigenèse n’est plus à démontrer, les mécanismes orientant le choix d’une inactivation génique par des phénomènes épigénétiques ou génétiques restent à déterminer.

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). HIC1is 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.