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Gene Review

HIC1  -  hypermethylated in cancer 1

Homo sapiens

Synonyms: Hic-1, Hypermethylated in cancer 1 protein, ZBTB29, ZNF901, Zinc finger and BTB domain-containing protein 29, ...
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Disease relevance of HIC1

  • We conclude that epigenetic TSG inactivation is a significant feature of medulloblastoma, and identify RASSF1A, HIC1 and CASP8 as potentially critical genes in its pathogenesis [1].
  • The methylation of the promoter region of the HIC1 gene in colorectal cancer was observed most frequently and could serve as a sensitive marker for colorectal cancer [2].
  • In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutations [3].
  • HIC1 methylation was more frequent in the aggressive alveolar subtype of rhabdomyosarcomas (100%, 8 of 8) than the embryonal subtype (33%, 4 of 12; P < 0.005) and was rare in the nonmalignant tissues examined [4].
  • Hypermethylation within the promoters of some genes appear to be an early event in the pathogenesis of neoplasia (ER, P15), while other genes seem to become methylated during the progression of leukemias (HIC1, c-abl) [5].

High impact information on HIC1

  • Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses [6].
  • Inhibition of SIRT1 function in cells without HIC1 abolishes the resistance to apoptosis [6].
  • Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, we speculate that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals [6].
  • We conclude that HIC1 is a candidate tumor-suppressor gene for which loss of function in both mouse and human cancers is associated only with epigenetic modifications [7].
  • The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor that belongs to a group of proteins known as the POZ family [7].

Chemical compound and disease context of HIC1

  • Using a demethylating drug 5-aza-2'-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer [8].
  • Therefore, we applied methylation-specific PCR of the 5'-untranslated region as well as of a central region of HIC-1 and bisulfite sequencing to determine the methylation status in 52 ependymomas of different histologic subtypes, grades and locations [9].

Biological context of HIC1

  • The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif [10].
  • HIC1 (hypermethylated in cancer) and its close relative HRG22 (HIC1-related gene on chromosome 22) encode transcriptional repressors with five C(2)H(2) zinc fingers and an N-terminal BTB/POZ autonomous transcriptional repression domain that is unable to recruit histone deacetylases (HDACs) [10].
  • The BTB/POZ domain does not interact with mCtBP1, but the dimerization of HIC1 through this domain is required for the interaction with mCtBP1 [10].
  • HIC1 strongly interacts with mCtBP1 both in vivo and in vitro through this conserved GLDLSKK motif, thus extending the CtBP consensus binding site [10].
  • In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum [1].

Anatomical context of HIC1


Associations of HIC1 with chemical compounds

  • When tethered to DNA by fusion with the Gal4 DNA-binding domain, the HIC1 central region represses transcription through interactions with CtBP in a trichostatin A-sensitive manner [10].
  • Alignment of the HIC1 and HRG22 proteins from various species highlighted a perfectly conserved GLDLSKK/R motif highly related to the consensus CtBP interaction motif (PXDLSXK/R), except for the replacement of the virtually invariant proline by a glycine [10].
  • CONCLUSIONS: Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin [13].
  • Treatment with the glycolytic blocker 2-deoxyglucose (2-DG) decreases association of the redox sensor CtBP with HIC1, an inhibitor of SIRT1 transcription [14].
  • Three human tumor cell lines were used in this study (MiaPaCa, DU145, and U251) and the methylation status of three genes frequently hypermethylated in tumor cells (RASSF1A, HIC-1, and 14-3-3sigma) was determined as a function of zebularine exposure [15].

Physical interactions of HIC1

  • Here, we show that HIC1 interacts with both CtBP1 and CtBP2 and that this interaction is stimulated by agents increasing NADH levels [16].

Enzymatic interactions of HIC1

  • HIC-1 is proposed to be commonly inactivated in human cancers by hypermethylation of a normally unmethylated dense CpG island which encompasses the entire gene [17].

Regulatory relationships of HIC1


Other interactions of HIC1


Analytical, diagnostic and therapeutic context of HIC1


  1. Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profiling. Lindsey, J.C., Lusher, M.E., Anderton, J.A., Bailey, S., Gilbertson, R.J., Pearson, A.D., Ellison, D.W., Clifford, S.C. Carcinogenesis (2004) [Pubmed]
  2. Heterogeneity of DNA methylation status analyzed by bisulfite-PCR-SSCP and correlation with clinico-pathological characteristics in colorectal cancer. Maekawa, M., Sugano, K., Ushiama, M., Fukayama, N., Nomoto, K., Kashiwabara, H., Fujita, S., Kakizoe, T. Clin. Chem. Lab. Med. (2001) [Pubmed]
  3. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Chen, W., Cooper, T.K., Zahnow, C.A., Overholtzer, M., Zhao, Z., Ladanyi, M., Karp, J.E., Gokgoz, N., Wunder, J.S., Andrulis, I.L., Levine, A.J., Mankowski, J.L., Baylin, S.B. Cancer Cell (2004) [Pubmed]
  4. Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Rathi, A., Virmani, A.K., Harada, K., Timmons, C.F., Miyajima, K., Hay, R.J., Mastrangelo, D., Maitra, A., Tomlinson, G.E., Gazdar, A.F. Clin. Cancer Res. (2003) [Pubmed]
  5. DNA methylation changes in hematologic malignancies: biologic and clinical implications. Issa, J.P., Baylin, S.B., Herman, J.G. Leukemia (1997) [Pubmed]
  6. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Chen, W.Y., Wang, D.H., Yen, R.C., Luo, J., Gu, W., Baylin, S.B. Cell (2005) [Pubmed]
  7. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Chen, W.Y., Zeng, X., Carter, M.G., Morrell, C.N., Chiu Yen, R.W., Esteller, M., Watkins, D.N., Herman, J.G., Mankowski, J.L., Baylin, S.B. Nat. Genet. (2003) [Pubmed]
  8. Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer. Nicoll, G., Crichton, D.N., McDowell, H.E., Kernohan, N., Hupp, T.R., Thompson, A.M. Br. J. Cancer (2001) [Pubmed]
  9. Analysis of HIC-1 methylation and transcription in human ependymomas. Waha, A., Koch, A., Hartmann, W., Mack, H., Schramm, J., Sörensen, N., Berthold, F., Wiestler, O.D., Pietsch, T., Waha, A. Int. J. Cancer (2004) [Pubmed]
  10. The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Deltour, S., Pinte, S., Guerardel, C., Wasylyk, B., Leprince, D. Mol. Cell. Biol. (2002) [Pubmed]
  11. HIC1 hypermethylation is a late event in hematopoietic neoplasms. Issa, J.P., Zehnbauer, B.A., Kaufmann, S.H., Biel, M.A., Baylin, S.B. Cancer Res. (1997) [Pubmed]
  12. KCTD11 expression in medulloblastoma is lower than in adult cerebellum and higher than in neural stem cells. Zawlik, I., Zakrzewska, M., Witusik, M., Golanska, E., Kulczycka-Wojdala, D., Szybka, M., Piaskowski, S., Wozniak, K., Zakrzewski, K., Papierz, W., Liberski, P.P., Rieske, P. Cancer Genet. Cytogenet. (2006) [Pubmed]
  13. Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Koul, S., McKiernan, J.M., Narayan, G., Houldsworth, J., Bacik, J., Dobrzynski, D.L., Assaad, A.M., Mansukhani, M., Reuter, V.E., Bosl, G.J., Chaganti, R.S., Murty, V.V. Mol. Cancer (2004) [Pubmed]
  14. Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Zhang, Q., Wang, S.Y., Fleuriel, C., Leprince, D., Rocheleau, J.V., Piston, D.W., Goodman, R.H. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  15. Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA methylation inhibitor zebularine. Dote, H., Cerna, D., Burgan, W.E., Carter, D.J., Cerra, M.A., Hollingshead, M.G., Camphausen, K., Tofilon, P.J. Clin. Cancer Res. (2005) [Pubmed]
  16. 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, K.G., Crossley, M., Leprince, D. FEBS J. (2006) [Pubmed]
  17. Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Fujii, H., Biel, M.A., Zhou, W., Weitzman, S.A., Baylin, S.B., Gabrielson, E. Oncogene (1998) [Pubmed]
  18. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Wales, M.M., Biel, M.A., el Deiry, W., Nelkin, B.D., Issa, J.P., Cavenee, W.K., Kuerbitz, S.J., Baylin, S.B. Nat. Med. (1995) [Pubmed]
  19. 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. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. Park, H.J., Yu, E., Shim, Y.H. Cancer Lett. (2006) [Pubmed]
  21. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Aggerholm, A., Holm, M.S., Guldberg, P., Olesen, L.H., Hokland, P. Eur. J. Haematol. (2006) [Pubmed]
  22. Association between CpG island methylation and microsatellite instability in colorectal cancer. Ahuja, N., Mohan, A.L., Li, Q., Stolker, J.M., Herman, J.G., Hamilton, S.R., Baylin, S.B., Issa, J.P. Cancer Res. (1997) [Pubmed]
  23. 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. Mol. Cell. Biol. (2007) [Pubmed]
  24. 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, B.R., Guérardel, C., Leprince, D. J. Biol. Chem. (2004) [Pubmed]
  25. 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, T.J., Tschan, M.P., Hügli, B., Reddy, V.A., Andres, A.C., Torbett, B.E., Tobler, A., Fey, M.F. Oncogene (2006) [Pubmed]
  26. Epigenetic silencing of the HIC-1 gene in human medulloblastomas. Waha, A., Waha, A., Koch, A., Meyer-Puttlitz, B., Weggen, S., Sörensen, N., Tonn, J.C., Albrecht, S., Goodyer, C.G., Berthold, F., Wiestler, O.D., Pietsch, T. J. Neuropathol. Exp. Neurol. (2003) [Pubmed]
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