Medicine in focus
HIC1 (Hypermethylated in Cancer 1) epigenetic silencing in tumors

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Abstract

HIC1 (Hypermethylated in Cancer 1), as it name implied, was originally isolated as a new candidate tumor suppressor gene located at 17p13.3 because it resides in a CpG island that is hypermethylated in many types of human cancers. HIC1 encodes a transcription factor associating an N-terminal BTB/POZ domain to five C-terminal Krüppel-like C2H2 zinc finger motifs. In this review, we will begin by providing an overview of the current knowledge on HIC1 function, mainly gained from in vitro studies, as a sequence-specific transcriptional repressor interacting with a still growing range of HDAC-dependent and HDAC-independent corepressor complexes. We will then summarize the studies that have demonstrated frequent hypermethylation changes or losses of heterozygosity of the HIC1 locus in human cancers. Next, we will review animal models which have firmly established HIC1 as a bona fide tumor suppressor gene epigenetically silenced and functionally cooperating notably with p53 within a complex HIC1-p53-SIRT1 regulatory loop. Finally, we will discuss how this epigenetic inactivation of HIC1 might “addict” cancer cells to altered survival and signaling pathways or to lineage-specific transcription factors during the early stages of tumorigenesis.

Introduction

For a long time cancer has been considered as a group of diseases driven by genetic modifications including chromosomal translocations, gene amplifications or point mutations in oncogenes or in tumor suppressor genes. However, it is now becoming increasingly clear that epigenetic changes, marked by DNA methylation and histone tail modifications, which convey heritable gene expression patterns, are also central to many human diseases including cancer.

DNA hypermethylation changes at the D17S5 locus in many cancers allowed the positional cloning of HIC1 (Hypermethylated in Cancer 1) as a candidate tumor suppressor located in 17p13.3, a region frequently hypermethylated or deleted in many types of prevalent human tumors (Wales et al., 1995). HIC1 encodes a transcription factor with five Krüppel-like C2H2 zinc finger motifs (Wales et al., 1995, Deltour et al., 1999, Deltour et al., 2002, Pinte et al., 2004b).

In this review, we will first provide an overview of the current understanding of HIC1 function as a sequence-specific transcriptional repressor. We will then describe the studies and animal models which unambiguously defined HIC1 as a tumor suppressor gene epigenetically silenced in many prevalent human cancers.

Section snippets

HIC1: genomic organization

From sequencing analyses of genomic clones and from functional assays, the exon–intron structures of the human and murine HIC1 genes appeared very similar with alternative first exons followed by a unique second exon, containing a coding region and a 3′ untranslated region (Carter et al., 2000, Guerardel et al., 2001). The human HIC1 genomic region contains three promoters that give rise to different alternatively spliced transcripts. Exon 1a is non-coding and associated with the major G–C rich

HIC1: functional aspects

The HIC1 protein is a sequence-specific transcriptional repressor containing three main functional domains (Fig. 2): (i) the N-terminal BTB/POZ (which stands for Broad complex, Tramtrack and Bric à brac/Poxviruses and Zinc finger) domain of about 120 amino-acid is a dimerization domain known to play direct or indirect (through conformational effects) roles in protein–protein interactions. This domain is also an autonomous transcriptional repression domain (Albagli et al., 1995, Stogios et al.,

Inactivation of HIC1 is frequent in cancers

From the beginning, the history of HIC1 has been directly linked to P53. Indeed, loss of heterozygosity (LOH) on the short arm of chromosome 17 (17p) is one of the most common genetic alterations in human cancers and allelic losses most often coincide with mutations in the TP53 gene at 17p13.1 (Ko and Prives, 1996). However, it became rapidly obvious that in breast and ovarian tumors, 17p allelic losses occur at high frequency in regions distal to TP53 and even in the absence of TP53 mutations.

Mouse models of Hic1 and cancer

The epigenetic silencing or deletion of HIC1 in numerous primary tumors and cell lines strongly suggested that it could be a new tumor suppressor gene. Unquestionable clues to the tumor suppressor function of HIC1 have come from the study of Hic1-deficient mice developed in Dr Baylin's laboratory (Chen et al., 2003). Building on this work, two double heterozygote models have shown that Hic1 can cooperate with p53 and Ptch1 in tumorigenesis (Chen et al., 2004, Briggs et al., 2008).

HIC1: a cancer stem cell gene pre-marked for aberrant silencing in ES cells

According to the cancer stem cell hypothesis which is now widely accepted, tumors contain and are driven by a minority cellular population which has retained key stem-cell properties including self-renewal, pluripotency and the ability to reinitiate the tumor mass containing the cellular heterogeneity observed in the original tumor (Jones and Baylin, 2007). Numerous studies have highlighted the key roles of epigenetic signatures in stem-cell identity (reviewed in (Spivakov and Fisher, 2007)).

Conclusions and future directions for research

Thirteen years after its discovery by Dr Baylin's laboratory, HIC1 is now well-recognized as a tumor suppressor gene modulating p53-dependent apoptotic DNA damage responses through direct binding to the SIRT1 promoter; cooperating with Patched, an inhibitor of the Hedgehog pathway to induce medulloblastomas and able to modulate the Wnt pathway.

Despite this significant progress, many basic questions remain unresolved. First, an incomplete picture exists for the mechanisms of transcriptional

Acknowledgements

This review is dedicated to the memory of Christian Lagrou and Jean Coll.

CF and GB were supported by predoctoral fellowships from the Ministère de l’Education Nationale et de la Recherche and from CNRS/Région Nord-Pas de Calais respectively. MT was supported by a post-doctoral fellowship from Association for International Cancer Research (AICR). Our work was supported by funds from CNRS, PASTEUR Institute of Lille, Ligue contre le Cancer (Comité Régional du Septentrion), ARC (Association pour

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