Download Gene Section HIC1 (hypermethylated in cancer 1) Atlas of Genetics and Cytogenetics

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Gene Section
Mini Review
HIC1 (hypermethylated in cancer 1)
Dominique Leprince
Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, BP 447, 59021 Lille Cedex, France
Published in Atlas Database: February 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/HIC1ID40819ch17p13.html
DOI: 10.4267/2042/38437
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Hugo: HIC1
Other names: ZBTB29
Location: 17p13.3.
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.
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 COS7 or HEK293 cells.
In human primary fibroblats (WI38), the endogenous
HIC1 proteins are localized in discrete nuclear
structures called 'HIC1 bodies'.
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.
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.
Transcription
Homology
3.0 Kb mRNA.
HIC1 shares distant homology through the conserved
BTB/POZ domain and C2H2 zinc fingers domain with
several BTB/POZ transcriptional repressors.
Pseudogene
No known pseudogene.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
192
HIC1 (hypermethylated in cancer 1)
Leprince D
tumor suppressor gene Hic1 exhibit developmental defects of
structures affected in the Miller-Dieker syndrome. Hum. Mol.
Genet 2000;9:413-419.
Mutations
Germinal
Deltour S, Pinte S, Guérardel C, Leprince D. Characterization
of HRG22, a human homologue of the putative tumor
suppressor gene HIC1. Biochem Biophys Res Commun
2001;287:427-434.
No germinal coding sequence mutations have been
described for HIC1.
Somatic
Guérardel C, Deltour S, Pinte S, Monte D, Begue A, Godwin
AK, Leprince D. Identification in the human candidate tumor
suppressor gene HIC-1 of a new major alternative TATA-less
promoter positively regulated by p53. J Biol Chem
2001;276:3078-3089.
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.
Deltour S, Pinte S, Guérardel C, Wasylyk B, Leprince D. The
human candidate tumor suppressor gene HIC1 recruits CtBP
through a degenerate GLDLSKK motif. Mol Cell Biol
2002;22:4890-4901.
Epigenetics
Chen WY, Zeng X., Carter M., Morrell CN, Chiu-Yen RW,
Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB.
Heterozygous disruption of Hic1 predisposes mice to a genderdependent spectrum of malignant tumors. Nature Genetics
2003;33:197-202.
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.
Chen W, Cooper TK, Zahnow CA, Overholtzer
Ladanyi M, Karp JE, Gokgoz N, Wunder JS,
Levine AJ, Mankowski JL, Baylin SB. Epigenetic
loss of Hic1 function accentuates the role
tumorigenesis. Cancer Cell 2004;6:387-398.
Implicated in
Pinte S, Guérardel C, Deltour-Balerdi S, Godwin AK, Leprince
D. Identification of a second G-C-rich promoter conserved in
the human, murine and rat tumor suppressor genes HIC1.
Oncogene 2004;23:4023-4031.
Medulloblastomas, breast tumours,
ovary tumours, prostate tumours
Pinte S, Stankovic-Valentin N, Deltour S, Rood BR, Guérardel
C, Leprince D. 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. J Biol Chem 2004;279:38313-38324.
Note: (see above).
Breakpoints
Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. HIC1
directly regulates SIRT1 to modulate p53-dependent DNAdamage responses. Cell 2005;123:437-448.
Note: No breakpoint in HIC1 identified so far.
To be noted
Britschgi C, Rizzi M, GrobTJ, Tschan MP, Hügli B, Reddy VA,
Andres AC, Torbett BE, Tobler A, Fey MF. Identification of the
p53 family-responsive element in the promoter region of the
tumor suppressor gene hypermethylated in cancer 1.
Oncogene 2006;25:2030-2039.
Note: 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.
Stankovic-Valentin N, Verger A, Deltour-Balerdi S, Quinlan KG,
Crossley M, Leprince D. A L225A substitution in the human
tumour suppressor HIC1 abolishes its interaction with the
corepressor CtBP. Febs J 2006;273:2879-2890.
Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V. HIC1
attenuates Wnt signaling by recruitment of TCF-4 and betacatenin to the nuclear bodies. Embo J 2006;25:2326-2337.
References
Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G,
Guérardel
C,
Dejean
A,
Leprince
D.
An
acetylation/deacetylation-SUMOylation switch through a
phylogenetically conserved psiKxEP motif in the tumor
suppressor HIC1 regulates transcriptional repression activity.
Mol Cell Biol 2007;27:in press.
Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee
WK, Kuerbitz SJ, Baylin SB. p53 activates expression of HIC1, a new candidate tumour suppressor gene on 17p13.3.
Nature Medicine 1995;1:570-577.
Deltour S, Guérardel C, Leprince D. Recruitment of SMRT/NCoR-mSin3A-HDAC-repressing complexes is not a general
mechanism for BTB/POZ transcriptional repressors: the case
of HIC-1 and gammaFBP-B. Proc Natl Acad Sci (USA)
1999;96:14831-14836.
Zhang Q, Wang SH, Fleuriel C, Leprince D, Rocheleau JV,
Piston DW, Goodman RH. Metabolic regulation of SIRT1
transcription via a HIC1:CtBP corepressor complex. Proc Natl
Acad Sci (USA) 2007;104:829-33.
Grimm C, Spörle R,.Schmid TE, Adler ID, Adamski J,
Schughart K, Graw J. Isolation and embryonic expression of
the novel mouse gene Hic1, the homologue of HIC1, a
candidate gene for the Miller-Dieker syndrome. Hum Mol
Genet 1999;8:697-710.
This article should be referenced as such:
Leprince D. HIC1 (hypermethylated in cancer 1). Atlas Genet
Cytogenet Oncol Haematol.2007;11(3):192-193.
Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski
JL, Donovan DM, Baylin SB. Mice deficient in the candidate
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
M, Zhao Z,
Andrulis IL,
and genetic
of p53 in
193