HIC1 (Hypermethylated in Cancer 1)

Identity

Other names	ZBTB29
HGNC	HIC1
Location	17p13.3.
Location_base_pair	Starts at 1906354 and ends at 1909731 bp from pter ( according to hg18-Mar_2006).
Local_order	Close to the D17S5/D17S30/YNZ22 micro satellite marker which is a highly polymorphic variable number of tandem repeats (VNTR) marker. Aberrant hypermethylation in tumours of a cluster of methylation-sensitive NotI restriction sites surrounding this marker allowed the positional cloning of HIC1 in 1995. Telomere, OVCA1/DPH2L1, OVCA2, HIC1, KIAA0732,......Centromere.

Note	OVCA1/DPH2L1 and OVCA2 are two tumour suppressor genes deleted in ovarian cancers.

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.

Protein

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

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.
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.

Implicated in

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

Breakpoints

Note	No breakpoint in HIC1 identified so far.

To be noted

A paralog called HIC2, HRG22 or KIAA1020 is found on human chromosome 22. It is located in 22q11.2 in a region subject to translocations (BCRL-2 for Breakpoint Cluster Region-Like 2). But so far, there is no experimental evidence for a translocation implicating HRG22 or for its aberrant hypermethylation in tumours.

External links

	Nomenclature
HGNC	HIC1   4909
Entrez_Gene	HIC1  3090  hypermethylated in cancer 1
	Cards
Atlas	HIC1ID40819ch17p13
GeneCards	HIC1
Ensembl	HIC1 [Search_View]   ENSG00000177374 [Gene_View]
Genatlas	HIC1
GeneLynx	HIC1
eGenome	HIC1
euGene	3090
	Genomic and cartography
GoldenPath	HIC1  -  17p13.3.   chr17:1906354-1909731 +  17p13.3   [Description]    (hg18-Mar_2006)
Ensembl	HIC1 - 17p13.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	HIC1
	Gene and transcription
Genbank	AJ550616 [ ENTREZ ]
Genbank	AJ583693 [ ENTREZ ]
Genbank	AJ583694 [ ENTREZ ]
Genbank	BC030208 [ ENTREZ ]
Genbank	BC156194 [ ENTREZ ]
RefSeq	NM_001098202 [ SRS ]    NM_001098202 [ ENTREZ ]
RefSeq	NM_006497 [ SRS ]    NM_006497 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010718 [ SRS ]    NT_010718 [ ENTREZ ]
RefSeq	NW_001838403 [ SRS ]    NW_001838403 [ ENTREZ ]
RefSeq	NW_926584 [ SRS ]    NW_926584 [ ENTREZ ]
AceView	HIC1 AceView - NCBI
Unigene	Hs.695682 [ SRS ]    Hs.695682 [ NCBI ]     HS695682 [ spliceNest ]
Fast-db	736 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O95459 [ SRS]    O95459 [ EXPASY ]     O95459 [ INTERPRO ]     O95459 [ UNIPROT ]
Prosite	PS00028 ZINC_FINGER_C2H2_1 [ SRS ]    PS00028 ZINC_FINGER_C2H2_1 [ Expasy ]
Prosite	PS50157 ZINC_FINGER_C2H2_2 [ SRS ]    PS50157 ZINC_FINGER_C2H2_2 [ Expasy ]
Interpro	IPR007087 Znf_C2H2 [ SRS ]    IPR007087 Znf_C2H2 [ EBI ]
Interpro	IPR015880 Znf_C2H2-like [ SRS ]    IPR015880 Znf_C2H2-like [ EBI ]
CluSTr	O95459
Smart	SM00355 ZnF_C2H2 [EMBL]
Blocks	O95459
HPRD	04826
	Protein Interaction databases
DIP	O95459
IntAct	O95459
	Polymorphism : SNP, mutations, diseases
OMIM	603825    [ map ]
GENECLINICS	603825
SNP	HIC1 [dbSNP-NCBI]
SNP	NM_001098202 [SNP-NCI]
SNP	NM_006497 [SNP-NCI]
SNP	HIC1 [GeneSNPs - Utah]  HIC1] [HGBASE - SRS]
HAPMAP	HIC1 [HAPMAP]
HGMD	HIC1
	General knowledge
Family Browser	HIC1 [UCSC Family Browser]
SOURCE	NM_001098202
SOURCE	NM_006497
SMD	Hs.695682
SAGE	Hs.695682
GO	transcription factor activity [Amigo]  transcription factor activity
GO	protein binding [Amigo]  protein binding
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	multicellular organismal development [Amigo]  multicellular organismal development
GO	zinc ion binding [Amigo]  zinc ion binding
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
GO	metal ion binding [Amigo]  metal ion binding
BIOCARTA	Hypoxia and p53 in the Cardiovascular system    [Genes]
PubGene	HIC1
TreeFam	HIC1
CTD	3090 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	HIC1 Related clones (RZPD - Berlin)
	PubMed
PubMed	23 Pubmed reference(s) in Entrez

Bibliography

p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3.

Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, Kuerbitz SJ, Baylin SB

Nature medicine. 1995 ; 1 (6) : 570-577.

PMID 7585125

Recruitment 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, Guerardel C, Leprince D

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (26) : 14831-14836.

PMID 10611298

Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.

Grimm C, Spˆrle R, Schmid TE, Adler ID, Adamski J, Schughart K, Graw J

Human molecular genetics. 1999 ; 8 (4) : 697-710.

PMID 10072440

Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome.

Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski JL, Donovan DM, Baylin SB

Human molecular genetics. 2000 ; 9 (3) : 413-419.

PMID 10655551

Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1.

Deltour S, Pinte S, Guˆİrardel C, Leprince D

Biochemical and biophysical research communications. 2001 ; 287 (2) : 427-434.

PMID 11554746

Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53.

Guerardel C, Deltour S, Pinte S, Monte D, Begue A, Godwin AK, Leprince D

The Journal of biological chemistry. 2001 ; 276 (5) : 3078-3089.

PMID 11073960

The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.

Deltour S, Pinte S, Guerardel C, Wasylyk B, Leprince D

Molecular and cellular biology. 2002 ; 22 (13) : 4890-4901.

PMID 12052894

Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors.

Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB

Nature genetics. 2003 ; 33 (2) : 197-202.

PMID 12539045

Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.

Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, Karp JE, Gokgoz N, Wunder JS, Andrulis IL, Levine AJ, Mankowski JL, Baylin SB

Cancer cell. 2004 ; 6 (4) : 387-398.

PMID 15488761

Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1.

Pinte S, Guˆİrardel C, Deltour-Balerdi S, Godwin AK, Leprince D

Oncogene. 2004 ; 23 (22) : 4023-4031.

PMID 15007385

The 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, Stankovic-Valentin N, Deltour S, Rood BR, Guˆİrardel C, Leprince D

The Journal of biological chemistry. 2004 ; 279 (37) : 38313-38324.

PMID 15231840

Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.

Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB

Cell. 2005 ; 123 (3) : 437-448.

PMID 16269335

Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1.

Britschgi C, Rizzi M, Grob TJ, Tschan MP, Hˆşgli B, Reddy VA, Andres AC, Torbett BE, Tobler A, Fey MF

Oncogene. 2006 ; 25 (14) : 2030-2039.

PMID 16301995

A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP.

Stankovic-Valentin N, Verger A, Deltour-Balerdi S, Quinlan KG, Crossley M, Leprince D

The FEBS journal. 2006 ; 273 (13) : 2879-2890.

PMID 16762039

HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies.

Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V

The EMBO journal. 2006 ; 25 (11) : 2326-2337.

PMID 16724116

An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.

Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guˆİrardel C, Dejean A, Leprince D

Molecular and cellular biology. 2007 ; 27 (7) : 2661-2675.

PMID 17283066

Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex.

Zhang Q, Wang SY, Fleuriel C, Leprince D, Rocheleau JV, Piston DW, Goodman RH

Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (3) : 829-833.

PMID 17213307

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Contributor(s)

Written	02-2007	Dominique Leprince

Citation

This paper should be referenced as such :

Leprince D . HIC1 (Hypermethylated in Cancer 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HIC1ID40819ch17p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Tue Oct 14 21:19:52 2008