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HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1)

Identity

HGNC (Hugo) HACE1
LocusID (NCBI) 57531
Location 6q16.3
Location_base_pair Starts at 105175968 and ends at 105307794 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Note HACE1 was first cloned by sequencing clones obtained from a fetal brain cDNA library, and was designated as KIAA1320 (Nagase et al., 2000). The cDNA encodes a 909 amino acid protein (GenBank: NM_020771.3).
Description The HACE1 gene is located on chromosome 6 (105175968-105307794); 24 exons.

Protein

 
  Schematic structure of the HACE1 protein. HACE1 contains six ankyrin repeats at the N terminus and a HECT domain at the C terminus. A cysteine residue essential for the ubiquitin ligase activity is at position 876.
Description Human HACE1 encodes HACE1 protein, which containing 909 amino acid residues (size ~103 kDa) (Anglesio et al., 2004). HACE1 possesses six N-terminal ankyrin repeats (amino acid: 64-93; 97-126; 130-159; 163-192; 196-227; 228-257) and a C-terminal HECT domain (amino acid: 572-909; active cysteine residue at position 876).
Expression Anglesio et al. showed that a 4,6-kb transcript of HACE1 with strong expression in heart, brain, placenta, pancreas, as well as adult and fetal kidney. HACE1 expression is virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney (Anglesio et al., 2004). Zhang et al. showed that HACE1 mRNA transcripts are ubiquitously expressed in normal human tissues; but the mRNA expression of HACE1 decreases markedly in breast, renal, thyroid, vulva and liver tumors compared to the organ-matched normal tissue samples from the same individuals. The transcripts are downregulated in almost all lines from the NCI-60 panel of human cancer cell lines compared to control HEK293 cells. Lower expression is strongly associated with hypermethylation of two CpG islands located upstream of the HACE1 locus (Zhang et al., 2007). HACE1 is also downregulated in natural killer/T-cell lymphoma of the nasal type (NKTCL) (Huang et al., 2010), colorectal cancer (Hibi et al., 2008) and gastric cancer (Sakata et al., 2009). However, the expression of HACE1 varies in different breast cancer cell lines (Kao et al., 2009). In neuroblastomas, low HACE1 expression is associated with worse overall survival, suggesting that HACE1 may function as a tumor suppressor (Diskin et al., 2012).
Localisation Anglesio et al. indicated that the subcellular localization of HACE1 is predominantly in the endoplasmic reticulum (ER) and cytosol, and a small amount of endogenous protein is also present in other fractions of NIH3T3 cells (Anglesio et al., 2004). Tang et al. showed that a fraction of HACE1 colocalizes with Golgi markers in HeLa and normal rat kidney (NRK) cells; the association of HACE1 with Golgi membranes is through interaction with Golgi Rab GTPases, in particular Rab1 (Tang et al., 2011).
Function Tumor suppressor
Anglesio et al. showed that HACE1 possesses intrinsic ubiquitin ligase activity, utilizing UBCH7 as a candidate partner E2 enzyme (Anglesio et al., 2004). Zhang et al. demonstrated that HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice resulted in the development of spontaneous, late-onset cancer. Their data suggested that HACE1 is involved in phosphorylation dependent degradation of cyclin D1, indicating a role for HACE1 in inhibiting cell cycle progression (Zhang et al., 2007).
HACE1 deficient mice are spontaneously prone to developing multiple malignant tumors in various organs (Zhang et al., 2007).
Degradation of Rac1
In 2011, Torrino et al. reported that HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitination. HACE1 expression increases the ubiquitination of Rac1 when the GTPase is activated. HACE1 is required for cytotoxic necrosis factor 1 (CNSF1)-mediated depletion of Rac1 and efficient invasion of endothelial cell monolayer by bacteria, suggesting that HACE1 plays a major role in host defense against pathogens (Torrino et al., 2011). Castillo-Lluva et al. further showed that HACE1 catalyzes polyubiquitination of Rac1 at lysine 147 following its activation by a migration stimulus, such as hepatocyte growth factor (HGF), resulting in Rac1 degradation by the proteasome. HACE1-depletion is accompanied by an increased total Rac1 level and accumulation of Rac1 in membrane ruffles. Furthermore, HACE1-depletion leads to enhanced cell migration, which may be significant for malignant conversion (Castillo-Lluva et al., 2012).
Golgi biogenesis
Tang et al. reported that HACE1 is targeted to the Golgi membrane through interactions with Rab proteins. The ubiquitin ligase activity of HACE1 in mitotic Golgi disassembly is required for subsequent post-mitotic Golgi membrane fusion. Depletion of HACE1 using small hairpin RNAs or expression of an inactive HACE1 mutant protein in cells impairs post-mitotic Golgi membrane fusion. The identification of HACE1 as a Golgi-localized ubiquitin ligase provides evidence that ubiquitin has a critical role in Golgi biogenesis during the cell cycle (Tang et al., 2011).
Repression of the RAR (retinoic acid receptor)-regulated transcription
HACE1 was isolated as a RARβ3 AB region interacting protein. HACE1 functionally represses the transcriptional activity of RARα1 and RARβ isoforms 1, 2 and 3, but not RARγ1 in luciferase reporter assays. In addition, HACE1 represses several endogenous RAR-regulated genes. The E3 ubiquitin ligase activity is not required for the repression effect of HACE1 on the transcriptional activity of RARβ3. HACE1 also inhibits the retinoic acid-dependent degradation of RARβ3. The repression of RAR-regulated transcription by HACE1 is possibly due to its ability to inhibit RA-induced degradation of RARs (Zhao et al., 2009).
Determinant of the equol-producing phenotype
HACE1 was identified in a genome-wide association study (GWAS) designed to find genetic factors associated with the equol-producing phenotype in Korean population. The authors identified 5 single-nucleotide polymorphisms in HACE1. Individuals with a minor allele of the most significant SNP rs6927608 did not produce equol. The interaction between equol production and the rs6927608 HACE1 SNP was significantly associated with systolic blood pressure. Finally, the authors concluded that equol production is linked to blood pressure, and HACE1 might be a determinant of the equol-producing phenotype (Hong et al., 2012).
Homology The HACE1 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Implicated in

Entity Sporadic Wilms' tumor
Note In 2004, Anglesio et al. analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. They showed that although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissues compared with adjacent normal kidney. Moreover, HACE1 expression is virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. Their data implicated that low expression of HACE1 was associated with sporadic Wilms' tumor (Anglesio et al., 2004).
In 2010, Slade et al. indentified a t(5;6)(q21;q21) translocation in a child with bilateral, young-onset Wilms' tumor. The 6q21 breakpoint transects and truncates HACE1, which has been implicated as a somatically inactivated target in Wilms tumorigenesis. To evaluate the contribution of HACE1 to Wilms' tumor predisposition, the gene was screened in 450 individuals with Wilms' tumor. One child with unilateral Wilms' tumor and a truncated HACE1 mutation was identified. It was concluded that constitutional disruption of HACE1 likely predisposes Wilms' tumor. However, HACE1 mutations are rare and therefore can only make a small contribution to Wilms' tumor incidence (Slade et al., 2010).
  
Entity Lymphoma
Note HACE1 is downregulated in natural killer/T-cell lymphoma of the nasal type (NKTCL) in both gene expression profiling and array-base comparative genomic hybridization analyses. Since HACE1 is the target of epigenetic inactivation in Wilms' tumor and has been proposed as a tumor suppressor gene in multiple human cancers, it is tempting to speculate that HACE1 might be involved in the pathogenesis of NKTCL (Huang et al., 2010).
  
Entity Colorectal carcinomas and gastric cancer
Note The methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 32 patients with colorectal cancer using quantitative methylation-specific PCR (qMSP), and the correlation between the methylation status and the clinic pathological findings was evaluated. The aberrant methylation of HACE1 was frequently observed in colorectal cancer. Thus HACE1 might act as a tumor suppressor in colorectal carcinomas and HACE1 methylation might present a malignant potential in colorectal cancer (Hibi et al., 2008). Similar research was performed in primary gastric carcinomas, and HACE1 was found frequently methylated in gastric carcinoma derived from male patients (Sakata et al., 2009).
  
Entity Breast cancer
Note Kao et al. utilized the whole-genome DNA microarrays to profile gene expression and DNA copy number alterations (CANs) in a collection of 52 widely used breast cancer cell lines, and comparisons were made to existing profiles of primary breast tumors. The expression level of HACE1 varies between different breast cancer cell lines. The contribution of HACE1 breast cancer biogenesis is still unclear (Kao et al., 2009).
  
Entity Neuroblastomas
Note In a genome-wide association study of 2817 neuroblastoma cases and 7473 controls, HACE1 and LIN28B were identified as two new associations at 6q16.
Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas are associated with worse overall survival. These data suggested that HACE1 might function as a tumor suppressor and LIN28B as an oncogene in advanced neuroblastomas (Diskin et al., 2012).
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615

External links

Nomenclature
HGNC (Hugo)HACE1   21033
Cards
AtlasHACE1ID44285ch6q16
Entrez_Gene (NCBI)HACE1  57531  HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
GeneCards (Weizmann)HACE1
Ensembl (Hinxton)ENSG00000085382 [Gene_View]  chr6:105175968-105307794 [Contig_View]  HACE1 [Vega]
ICGC DataPortalENSG00000085382
AceView (NCBI)HACE1
Genatlas (Paris)HACE1
WikiGenes57531
SOURCE (Princeton)NM_020771
Genomic and cartography
GoldenPath (UCSC)HACE1  -  6q16.3   chr6:105175968-105307794 -  6q21   [Description]    (hg19-Feb_2009)
EnsemblHACE1 - 6q21 [CytoView]
Mapping of homologs : NCBIHACE1 [Mapview]
OMIM610876   
Gene and transcription
Genbank (Entrez)AB037741 AJ420474 AK124268 AK131207 AK291760
RefSeq transcript (Entrez)NM_020771
RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NT_025741 NW_001838988 NW_004929328
Consensus coding sequences : CCDS (NCBI)HACE1
Cluster EST : UnigeneHs.434340 [ NCBI ]
CGAP (NCI)Hs.434340
Alternative Splicing : Fast-db (Paris)GSHG0026804
Alternative Splicing GalleryENSG00000085382
Gene ExpressionHACE1 [ NCBI-GEO ]     HACE1 [ SEEK ]   HACE1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8IYU2 (Uniprot)
NextProtQ8IYU2  [Medical]
With graphics : InterProQ8IYU2
Splice isoforms : SwissVarQ8IYU2 (Swissvar)
Catalytic activity : Enzyme6.3.2.- [ Enzyme-Expasy ]   6.3.2.-6.3.2.- [ IntEnz-EBI ]   6.3.2.- [ BRENDA ]   6.3.2.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)    HECT (PS50237)   
Domains : Interpro (EBI)Ankyrin_rpt    Ankyrin_rpt-contain_dom    HECT   
Related proteins : CluSTrQ8IYU2
Domain families : Pfam (Sanger)Ank_2 (PF12796)    HECT (PF00632)   
Domain families : Pfam (NCBI)pfam12796    pfam00632   
Domain families : Smart (EMBL)ANK (SM00248)  HECTc (SM00119)  
DMDM Disease mutations57531
Blocks (Seattle)Q8IYU2
Human Protein AtlasENSG00000085382
Peptide AtlasQ8IYU2
HPRD17086
IPIIPI00337371   IPI00829725   IPI00642351   IPI00973324   IPI00903092   IPI00976386   IPI00980068   IPI00978260   IPI00974395   IPI00984714   IPI00978865   
Protein Interaction databases
DIP (DOE-UCLA)Q8IYU2
IntAct (EBI)Q8IYU2
FunCoupENSG00000085382
BioGRIDHACE1
IntegromeDBHACE1
STRING (EMBL)HACE1
Ontologies - Pathways
QuickGOQ8IYU2
Ontology : AmiGOGolgi membrane  ubiquitin-protein transferase activity  nucleus  endoplasmic reticulum  transcription, DNA-templated  regulation of transcription, DNA-templated  Golgi organization  cell cycle  protein ubiquitination  Rac protein signal transduction  ligase activity  Rab GTPase binding  regulation of cell migration  Golgi cisterna membrane  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  Rac GTPase binding  membrane fusion  protein K48-linked ubiquitination  
Ontology : EGO-EBIGolgi membrane  ubiquitin-protein transferase activity  nucleus  endoplasmic reticulum  transcription, DNA-templated  regulation of transcription, DNA-templated  Golgi organization  cell cycle  protein ubiquitination  Rac protein signal transduction  ligase activity  Rab GTPase binding  regulation of cell migration  Golgi cisterna membrane  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  Rac GTPase binding  membrane fusion  protein K48-linked ubiquitination  
Protein Interaction DatabaseHACE1
Wikipedia pathwaysHACE1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)HACE1
SNP (GeneSNP Utah)HACE1
SNP : HGBaseHACE1
Genetic variants : HAPMAPHACE1
1000_GenomesHACE1 
ICGC programENSG00000085382 
CONAN: Copy Number AnalysisHACE1 
Somatic Mutations in Cancer : COSMICHACE1 
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
DECIPHER (Syndromes)6:105175968-105307794
Mutations and Diseases : HGMDHACE1
OMIM610876   
MedgenHACE1
GENETestsHACE1
Disease Genetic AssociationHACE1
Huge Navigator HACE1 [HugePedia]  HACE1 [HugeCancerGEM]
Genomic VariantsHACE1  HACE1 [DGVbeta]
Exome VariantHACE1
dbVarHACE1
ClinVarHACE1
snp3D : Map Gene to Disease57531
General knowledge
Homologs : HomoloGeneHACE1
Homology/Alignments : Family Browser (UCSC)HACE1
Phylogenetic Trees/Animal Genes : TreeFamHACE1
Chemical/Protein Interactions : CTD57531
Chemical/Pharm GKB GenePA134983914
Clinical trialHACE1
Cancer Resource (Charite)ENSG00000085382
Other databases
Probes
Litterature
PubMed30 Pubmed reference(s) in Entrez
CoreMineHACE1
GoPubMedHACE1
iHOPHACE1

Bibliography

Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro.
Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O.
DNA Res. 2000 Feb 28;7(1):65-73.
PMID 10718198
 
Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney.
Anglesio MS, Evdokimova V, Melnyk N, Zhang L, Fernandez CV, Grundy PE, Leach S, Marra MA, Brooks-Wilson AR, Penninger J, Sorensen PH.
Hum Mol Genet. 2004 Sep 15;13(18):2061-74. Epub 2004 Jul 14.
PMID 15254018
 
The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers.
Zhang L, Anglesio MS, O'Sullivan M, Zhang F, Yang G, Sarao R, Mai PN, Cronin S, Hara H, Melnyk N, Li L, Wada T, Liu PP, Farrar J, Arceci RJ, Sorensen PH, Penninger JM.
Nat Med. 2007 Sep;13(9):1060-9. Epub 2007 Aug 12.
PMID 17694067
 
Aberrant methylation of the HACE1 gene is frequently detected in advanced colorectal cancer.
Hibi K, Sakata M, Sakuraba K, Shirahata A, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, Nemoto H, Sanada Y.
Anticancer Res. 2008 May-Jun;28(3A):1581-4.
PMID 18630515
 
Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery.
Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, Kwei KA, Hernandez-Boussard T, Wang P, Gazdar AF, Minna JD, Pollack JR.
PLoS One. 2009 Jul 3;4(7):e6146. doi: 10.1371/journal.pone.0006146.
PMID 19582160
 
Methylation of HACE1 in gastric carcinoma.
Sakata M, Kitamura YH, Sakuraba K, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, Nemoto H, Sanada Y, Hibi K.
Anticancer Res. 2009 Jun;29(6):2231-3.
PMID 19528486
 
HACE1: A novel repressor of RAR transcriptional activity.
Zhao J, Zhang Z, Vucetic Z, Soprano KJ, Soprano DR.
J Cell Biochem. 2009 Jun 1;107(3):482-93. doi: 10.1002/jcb.22146.
PMID 19350571
 
Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.
Huang Y, de Reynies A, de Leval L, Ghazi B, Martin-Garcia N, Travert M, Bosq J, Briere J, Petit B, Thomas E, Coppo P, Marafioti T, Emile JF, Delfau-Larue MH, Schmitt C, Gaulard P.
Blood. 2010 Feb 11;115(6):1226-37. doi: 10.1182/blood-2009-05-221275. Epub 2009 Nov 30.
PMID 19965620
 
Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene.
Slade I, Stephens P, Douglas J, Barker K, Stebbings L, Abbaszadeh F, Pritchard-Jones K; FACT collaboration, Cole R, Pizer B, Stiller C, Vujanic G, Scott RH, Stratton MR, Rahman N.
J Med Genet. 2010 May;47(5):342-7. doi: 10.1136/jmg.2009.072983. Epub 2009 Nov 30.
PMID 19948536
 
The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle.
Tang D, Xiang Y, De Renzis S, Rink J, Zheng G, Zerial M, Wang Y.
Nat Commun. 2011 Oct 11;2:501. doi: 10.1038/ncomms1509.
PMID 21988917
 
The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1.
Torrino S, Visvikis O, Doye A, Boyer L, Stefani C, Munro P, Bertoglio J, Gacon G, Mettouchi A, Lemichez E.
Dev Cell. 2011 Nov 15;21(5):959-65. doi: 10.1016/j.devcel.2011.08.015. Epub 2011 Oct 27.
PMID 22036506
 
The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation.
Castillo-Lluva S, Tan CT, Daugaard M, Sorensen PH, Malliri A.
Oncogene. 2012 May 21. doi: 10.1038/onc.2012.189. [Epub ahead of print]
PMID 22614015
 
Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.
Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, Diamond M, Carpenter EL, Winter C, Lee H, Jagannathan J, Latorre V, Iolascon A, Hakonarson H, Devoto M, Maris JM.
Nat Genet. 2012 Oct;44(10):1126-30. doi: 10.1038/ng.2387. Epub 2012 Sep 2.
PMID 22941191
 
Epidemiological profiles between equol producers and nonproducers: a genomewide association study of the equol-producing phenotype.
Hong KW, Ko KP, Ahn Y, Kim CS, Park SJ, Park JK, Kim SS, Kim Y.
Genes Nutr. 2012 Oct;7(4):567-74. Epub 2012 Apr 3.
PMID 22477055
 
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Contributor(s)

Written12-2012Feng Cui, Yanzhuang Wang
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048, USA

Citation

This paper should be referenced as such :
Cui, F ; Wang, Y
HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(5):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/HACE1ID44285ch6q16.html

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indexed on : Sat Nov 8 16:58:34 CET 2014

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