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HIC1 (Hypermethylated in Cancer 1)

Written2007-02Dominique Leprince
Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, BP 447, 59021 Lille Cedex, France

(Note : for Links provided by Atlas : click)

Identity

Alias_nameshypermethylated in cancer 1
Alias_symbol (synonym)ZBTB29
ZNF901
Other alias
HGNC (Hugo) HIC1
LocusID (NCBI) 3090
Atlas_Id 40819
Location 17p13.3  [Link to chromosome band 17p13]
Location_base_pair Starts at 1959604 and ends at 1962981 bp from pter ( according to hg19-Feb_2009)  [Mapping HIC1.png]
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.
Fusion genes
(updated 2016)
HIC1 (17p13.3) / OVCA2 (17p13.3)
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

Note
  
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.

Bibliography

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, Hügli B, Reddy VA, Andres AC, Torbett BE, Tobler A, Fey MF
Oncogene. 2006 ; 25 (14) : 2030-2039.
PMID 16301995
 
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
 
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
 
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
 
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
 
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
 
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
 
Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.
Grimm C, Spörle R, Schmid TE, Adler ID, Adamski J, Schughart K, Graw J
Human molecular genetics. 1999 ; 8 (4) : 697-710.
PMID 10072440
 
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
 
Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1.
Pinte S, Guérardel 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, Guérardel C, Leprince D
The Journal of biological chemistry. 2004 ; 279 (37) : 38313-38324.
PMID 15231840
 
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, Guérardel C, Dejean A, Leprince D
Molecular and cellular biology. 2007 ; 27 (7) : 2661-2675.
PMID 17283066
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Leprince, D
HIC1 (hypermethylated in Cancer 1)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):192-193.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/HIC1ID40819ch17p13.html


External links

Nomenclature
HGNC (Hugo)HIC1   4909
Cards
AtlasHIC1ID40819ch17p13
Entrez_Gene (NCBI)HIC1  3090  hypermethylated in cancer 1
AliasesZBTB29; ZNF901; hic-1
GeneCards (Weizmann)HIC1
Ensembl hg19 (Hinxton)ENSG00000177374 [Gene_View]  chr17:1959604-1962981 [Contig_View]  HIC1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000177374 [Gene_View]  chr17:1959604-1962981 [Contig_View]  HIC1 [Vega]
ICGC DataPortalENSG00000177374
TCGA cBioPortalHIC1
AceView (NCBI)HIC1
Genatlas (Paris)HIC1
WikiGenes3090
SOURCE (Princeton)HIC1
Genetics Home Reference (NIH)HIC1
Genomic and cartography
GoldenPath hg19 (UCSC)HIC1  -     chr17:1959604-1962981 +  17p13.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)HIC1  -     17p13.3   [Description]    (hg38-Dec_2013)
EnsemblHIC1 - 17p13.3 [CytoView hg19]  HIC1 - 17p13.3 [CytoView hg38]
Mapping of homologs : NCBIHIC1 [Mapview hg19]  HIC1 [Mapview hg38]
OMIM603825   
Gene and transcription
Genbank (Entrez)AJ550616 AJ583693 AJ583694 BC030208 BC156194
RefSeq transcript (Entrez)NM_001098202 NM_006497
RefSeq genomic (Entrez)NC_000017 NC_018928 NG_027689 NT_010718 NW_004929405
Consensus coding sequences : CCDS (NCBI)HIC1
Cluster EST : UnigeneHs.695682 [ NCBI ]
CGAP (NCI)Hs.695682
Alternative Splicing GalleryENSG00000177374
Gene ExpressionHIC1 [ NCBI-GEO ]   HIC1 [ EBI - ARRAY_EXPRESS ]   HIC1 [ SEEK ]   HIC1 [ MEM ]
Gene Expression Viewer (FireBrowse)HIC1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3090
GTEX Portal (Tissue expression)HIC1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14526   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14526  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14526
Splice isoforms : SwissVarQ14526
PhosPhoSitePlusQ14526
Domaine pattern : Prosite (Expaxy)BTB (PS50097)    ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)BTB/POZ_dom    HIC1    SKP1/BTB/POZ    Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domain families : Pfam (Sanger)BTB (PF00651)    zf-C2H2 (PF00096)    zf-C2H2_6 (PF13912)   
Domain families : Pfam (NCBI)pfam00651    pfam00096    pfam13912   
Domain families : Smart (EMBL)BTB (SM00225)  ZnF_C2H2 (SM00355)  
Conserved Domain (NCBI)HIC1
DMDM Disease mutations3090
Blocks (Seattle)HIC1
SuperfamilyQ14526
Human Protein AtlasENSG00000177374
Peptide AtlasQ14526
HPRD04826
IPIIPI00007993   IPI00219932   IPI00816072   IPI00979822   
Protein Interaction databases
DIP (DOE-UCLA)Q14526
IntAct (EBI)Q14526
FunCoupENSG00000177374
BioGRIDHIC1
STRING (EMBL)HIC1
ZODIACHIC1
Ontologies - Pathways
QuickGOQ14526
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  chromatin  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleoplasm  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  multicellular organism development  intrinsic apoptotic signaling pathway in response to DNA damage  Wnt signaling pathway  negative regulation of Wnt signaling pathway  histone deacetylase binding  positive regulation of DNA damage response, signal transduction by p53 class mediator  sequence-specific DNA binding  metal ion binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  chromatin  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleoplasm  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  multicellular organism development  intrinsic apoptotic signaling pathway in response to DNA damage  Wnt signaling pathway  negative regulation of Wnt signaling pathway  histone deacetylase binding  positive regulation of DNA damage response, signal transduction by p53 class mediator  sequence-specific DNA binding  metal ion binding  
Pathways : BIOCARTAHypoxia and p53 in the Cardiovascular system [Genes]   
NDEx NetworkHIC1
Atlas of Cancer Signalling NetworkHIC1
Wikipedia pathwaysHIC1
Orthology - Evolution
OrthoDB3090
GeneTree (enSembl)ENSG00000177374
Phylogenetic Trees/Animal Genes : TreeFamHIC1
HOVERGENQ14526
HOGENOMQ14526
Homologs : HomoloGeneHIC1
Homology/Alignments : Family Browser (UCSC)HIC1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerHIC1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HIC1
dbVarHIC1
ClinVarHIC1
1000_GenomesHIC1 
Exome Variant ServerHIC1
ExAC (Exome Aggregation Consortium)HIC1 (select the gene name)
Genetic variants : HAPMAP3090
Genomic Variants (DGV)HIC1 [DGVbeta]
DECIPHER (Syndromes)17:1959604-1962981  ENSG00000177374
CONAN: Copy Number AnalysisHIC1 
Mutations
ICGC Data PortalHIC1 
TCGA Data PortalHIC1 
Broad Tumor PortalHIC1
OASIS PortalHIC1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHIC1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDHIC1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch HIC1
DgiDB (Drug Gene Interaction Database)HIC1
DoCM (Curated mutations)HIC1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HIC1 (select a term)
intoGenHIC1
NCG5 (London)HIC1
Cancer3DHIC1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603825   
Orphanet4054   
MedgenHIC1
Genetic Testing Registry HIC1
NextProtQ14526 [Medical]
TSGene3090
GENETestsHIC1
Huge Navigator HIC1 [HugePedia]
snp3D : Map Gene to Disease3090
BioCentury BCIQHIC1
ClinGenHIC1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3090
Chemical/Pharm GKB GenePA29282
Clinical trialHIC1
Miscellaneous
canSAR (ICR)HIC1 (select the gene name)
Probes
Litterature
PubMed55 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHIC1
EVEXHIC1
GoPubMedHIC1
iHOPHIC1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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