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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS 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