HIC1 (Hypermethylated in Cancer 1)

2007-02-01   Dominique Leprince 

Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, BP 447, 59021 Lille Cedex, France

Identity

HGNC
LOCATION
17p13.3
LOCUSID
ALIAS
ZBTB29,ZNF901,hic-1
FUSION GENES

DNA/RNA

Description

The HIC1 gene extends approximately 15 Kbp and consists of four exons. The first three exons 1a, 1b and 1c are alternative. Note that exon 1a is included in exon 1c. The major transcripts are derived from alternative promoters associated with exon 1a and 1b. Exon 1c is conserved in rodent genomes (rat and mice) but transcripts containing it are very minor.
The fourth exon, exon 2, contains the coding region and the 3 untranslated region.
An in-frame upstream ATG initiation codon is also found in exon 1b. This upstream reading frame is conserved in mice.

Transcription

3.0Kb mRNA.

Pseudogene

No known pseudogene.

Proteins

Description

714 amino acids; around 80kDa; Transcription factor belonging to the BTB/POZ and Krüppel C2H2 zinc fingers family. There is no experimental evidence for the existence of a protein initiated by the upstream ATG (e.g. through the use of antipeptide specific antibodies).

Expression

Based on Northern Blots and RT-PCR experiments, HIC1 is widely expressed in various normal tissues.

Localisation

Nucleus. Localized on nuclear dots upon overexpression by transient transfection assays in COS-7 or HEK293 cells. In human primary fibroblats (WI38), the endogenous HIC1 proteins are localized in discrete nuclear structures called "HIC1 bodies".

Function

HIC1 is a transcriptional repressor belonging to the BTB/POZ and Krüppel C2H2 family (44 proteins in the human genome). HIC1 interacts with the corepressor CtBP through a conserved GLDLSKK motif in the central region. This central region also contains a SUMOylation site MK314HEP which is important for the transcriptional repression potential of HIC1. This K314 is also subject to a reversible acetylation/deacetylation implicating CBP/P300 and the NAD+ dependent class III deacetylase SIRT1.

Homology

HIC1 shares distant homology through the conserved BTB/POZ domain and C2H2 zinc fingers domain with several BTB/POZ transcriptional repressors.

Mutations

Germinal

No germinal coding sequence mutation have been described for HIC1.

Somatic

No somatic coding sequence mutations have been described for HIC1 with one exception. During the screening of a panel of 68 medulloblastomas using SSCP analyses, a 12-bp deletion in the second exon of HIC1 has been identified. This results in a deletion of 4 glycine residues in a stretch of 8 located just after the BTB/POZ domain. The other regions of the protein specially the downstream central region and the zinc fingers domain are not affected by this deletion.

Epigenetics

There are a number of reports highlighting differences in promoter methylation status in primary human tumours (breast, ovaries, prostate, .....) compared to matched normal tissues, hence the name of the gene.

Implicated in

Entity name
medulloblastomas, breast tumours, ovary tumours, prostate tumours
Note
(see above)

Bibliography

Pubmed IDLast YearTitleAuthors
163019952006Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1.Britschgi C et al
106555512000Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome.Carter MG et al
154887612004Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.Chen W et al
162693352005Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.Chen WY et al
125390452003Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors.Chen WY et al
106112981999Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B.Deltour S et al
120528942002The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.Deltour S et al
100724401999Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.Grimm C et al
110739602001Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53.Guerardel C et al
150073852004Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1.Pinte S et al
152318402004The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties.Pinte S et al
172830662007An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.Stankovic-Valentin N et al
167241162006HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies.Valenta T et al
75851251995p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3.Wales MM et al
172133072007Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex.Zhang Q et al

Other Information

Locus ID:

NCBI: 3090
MIM: 603825
HGNC: 4909
Ensembl: ENSG00000177374

Variants:

dbSNP: 3090
ClinVar: 3090
TCGA: ENSG00000177374
COSMIC: HIC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000177374ENST00000322941Q14526
ENSG00000177374ENST00000399849Q14526
ENSG00000177374ENST00000571875V9GYA4
ENSG00000177374ENST00000571990I3L388
ENSG00000177374ENST00000574370Q70SM2
ENSG00000177374ENST00000576444K7ENQ1
ENSG00000177374ENST00000619757Q14526

Expression (GTEx)

0
5
10
15
20
25
30
35

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
172830662007An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.59
154887612004Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.49
196492062009Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.44
205477552010Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells.36
120528942002The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.35
120528942002The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.35
167241162006HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies.35
106112981999Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B.34
195252232009Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1).31
152318402004The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties.29

Citation

Dominique Leprince

HIC1 (Hypermethylated in Cancer 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/gene/40819/hic1-(hypermethylated-in-cancer-1)