Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 140 No. 4344 (2010)

Inactivation of the hypermethylated in cancer 1 tumour suppressor – not just a question of promoter hypermethylation?

  • M Jenal
  • C Britschgi
  • MF Fey
  • MP Tschan
Cite this as:
Swiss Med Wkly. 2010;140:w13106


The chromosomal region 17p13.3 is frequently deleted or epigenetically silenced in a variety of human cancers. It includes the hypermethylated in cancer 1 (HIC1) gene placed telomerically to the p53 tumour suppressor gene. HIC1 encodes a transcriptional repressor, and its targets identified to date are genes involved in proliferation, tumour growth and angiogenesis. In addition, HIC1 functionally cooperates with p53 to suppress cancer development.

Frequent allelic loss at position 17p13.1 in human cancers often points to mutations of the tumour suppressor p53. However, in a variety of cancer types, allelic loss of the short arm of chromosome 17 may hit regions distal to p53 and, interestingly, without leading to p53 mutations. Furthermore, the neighbouring region 17p13.3 often shows loss of heterozygosity or DNA hypermethylation in various types of solid tumours and leukaemias. In line with this concept, Wales et al. described a new potential tumour suppressor in this region and named it hypermethylated in cancer 1 (HIC1). Further, it was shown that in the majority of cases hypermethylation of this chromosomal region leads to epigenetic inactivation of HIC1.

A role for HIC1 in tumour development is further supported by a mouse model, since various spontaneous, age- and gender-specific malignant tumours occur in heterozygous Hic1 +/– knockout mice. Furthermore, exogenously delivered HIC1leads to a significant decrease in clonogenic survival in cancer cell lines. This review highlights the role of HIC1 inactivation in solid tumours and particularly in leukaemia development.


  1. Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski JL, Donovan DM, Baylin SB. Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Hum Mol Genet. 2000;9:413–9.
  2. Guerardel 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;276:3078–89.
  3. Pinte S, Guerardel 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;23:4023–31.
  4. Mondal AM, Chinnadurai S, Datta K, Chauhan SS, Sinha S, Chattopadhyay P. Identification and functional characterization of a novel unspliced transcript variant of HIC-1 in human cancer cells exposed to adverse growth conditions. Cancer Res. 2006;66:10466–77.
  5. Deltour S, Guerardel C, Leprince D. 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. Proc Natl Acad Sci. USA 1999;96:14831–6.
  6. Pinte S, Stankovic-Valentin N, Deltour S, Rood BR, Guerardel 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;279:38313–24.
  7. Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, et al. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995;1:570–7.
  8. Deltour S, Pinte S, Guerardel C, Wasylyk B, Leprince D. The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Mol Cell Biol. 2002;22:4890–901.
  9. 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;273:2879–90.
  10. Britschgi C, Rizzi M, Grob TJ, Tschan MP, Hugli B, Reddy VA, et al. Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. Oncogene. 2006;25:2030–9.
  11. Jenal M, Trinh E, Britschgi C, Britschgi A, Roh V, Vorburger SA, et al. The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1. Mol Cancer Res. 2009;7:916–22.
  12. Putzer BM. E2F1 death pathways as targets for cancer therapy. J Cell Mol Med. 2007;11:239–51.
  13. Fleuriel C, Touka M, Boulay G, Guerardel C, Rood BR, Leprince D. HIC1 (Hypermethylated in Cancer 1) epigenetic silencing in tumors. Int J Biochem Cell Biol. 2009;41:26–33.
  14. Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell. 2005;123:437–48.
  15. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, Nagy TR. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007;67:6612–8.
  16. Stocklein H, Smardova J, Macak J, Katzenberger T, Holler S, Wessendorf S, et al. Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma. Oncogene. 2008;27:2613–25.
  17. Briones VR, Chen S, Riegel AT, Lechleider RJ. Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta. Biochem Biophys Res Commun. 2006;345:595–601.
  18. Aigner A, Renneberg H, Bojunga J, Apel J, Nelson PS, Czubayko F. Ribozyme-targeting of a secreted FGF-binding protein (FGF-BP) inhibits proliferation of prostate cancer cells in vitro and in vivo. Oncogene. 2002;21:5733–42.
  19. Briggs KJ, Corcoran-Schwartz IM, Zhang W, Harcke T, Devereux WL, Baylin SB, et al. Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes Dev. 2008;22:770–85.
  20. Van Rechem C, Rood BR, Touka M, Pinte S, Jenal M, Guerardel C, et al. Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1). J Biol Chem. 2009;284:20927–35.
  21. Miao Z, Luker, K.E., Summers, B.C., Berahovich, R., Bhojani, M.S., Rehemtulla, A., Kleer, C.G., Essner, J.J., Nasevicius, A., Luker, G.D., Howard, M.C., Schall, T.J. (2007) CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A 104, 15735-40.
  22. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–13.
  23. Zhang W, Zeng X, Briggs KJ, Beaty R, Simons B, Chiu Yen RW, et al. A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene. 2010;29:2467–76.
  24. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10:165–80.
  25. Zhang B, Chambers KJ, Leprince D, Faller DV, Wang S. Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene. 2009;28:651–61.
  26. Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V. HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. EMBO J. 2006;25:2326–37.
  27. Van Rechem C, Boulay G, Pinte S, Stankovic-Valentin N, Guerardel C, Leprince D. Differential regulation of HIC1 target genes by CtBP and NuRD, via an Acetylation/SUMOylation switch, in quiescent versus proliferating cells. Mol Cell Biol.
  28. Pateras IS, Apostolopoulou K, Niforou K, Kotsinas A, Gorgoulis VG. p57KIP2: “Kip”ing the cell under control. Mol Cancer Res. 2009;7:1902–19.
  29. Kanai Y, Hui AM, Sun L, Ushijima S, Sakamoto M, Tsuda H, Hirohashi S. DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology. 1999;29:703–9.
  30. Fujii H, Biel MA, Zhou W, Weitzman SA, Baylin SB, Gabrielson E. Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Oncogene. 1998;16:2159–64.
  31. Nishida N, Nagasaka T, Nishimura T, Ikai I, Boland CR, Goel A. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology. 2008;47:908–18.
  32. Rood BR, Zhang H, Weitman DM, Cogen PH. Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res. 2002;62:3794–7.
  33. Uhlmann K, Rohde K, Zeller C, Szymas J, Vogel S, Marczinek K, et al. Distinct methylation profiles of glioma subtypes. Int J Cancer. 2003;106:52–9.
  34. Morton RA Jr, Watkins JJ, Bova GS, Wales MM, Baylin SB, Isaacs WB. Hypermethylation of chromosome 17P locus D17S5 in human prostate tissue. J Urol. 1996;156:512–6.
  35. Issa JP, Zehnbauer BA, Kaufmann SH, Biel MA, Baylin SB. HIC1 hypermethylation is a late event in hematopoietic neoplasms. Cancer Res. 1997;57:1678–81.
  36. Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell 2004;6:387–98.
  37. Ekmekci CG, Gutierrez MI, Siraj AK, Ozbek U, Bhatia K. Aberrant methylation of multiple tumor suppressor genes in acute myeloid leukemia. Am J Hematol. 2004;77:233–40.
  38. Grovdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, et al. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010.
  39. Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol. 2006;76:23–32.
  40. Deneberg S, Grovdal M, Karimi M, Jansson M, Nahi H, Corbacioglu A, et al. Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia. Leukemia. 2010;24:932–41.
  41. Melki JR, Vincent PC, Clark SJ. Cancer-specific region of hypermethylation identified within the HIC1 putative tumour suppressor gene in acute myeloid leukaemia. Leukemia. 1999;13:877–3.
  42. Britschgi C, Jenal M, Rizzi M, Mueller BU, Torbett BE, Andres AC, et al. HIC1 tumour suppressor gene is suppressed in acute myeloid leukaemia and induced during granulocytic differentiation. Br J Haematol. 2008;141:179–87.
  43. Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet. 2003;33:197–202.
  44. Ahuja N, Mohan AL, Li Q, Stolker JM, Herman JG, Hamilton SR, et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 1997;57:3370–4.
  45. Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007;132:127–38.
  46. Nosho K, Kure S, Irahara N, Shima K, Baba Y, Spiegelman D, et al. A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology. 2009;137:1609–20 e1-3.
  47. Eguchi K, Kanai Y, Kobayashi K, Hirohashi S. DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history. Cancer Res. 1997;57:4913–5.
  48. Parrella P, Scintu M, Prencipe M, Poeta ML, Gallo AP, Rabitti C, et al. HIC1 promoter methylation and 17p13.3 allelic loss in invasive ductal carcinoma of the breast. Cancer Lett. 2005;222:75–81.
  49. Gustafson KS, Furth EE, Heitjan DF, Fansler ZB, Clark DP. DNA methylation profiling of cervical squamous intraepithelial lesions using liquid-based cytology specimens: an approach that utilizes receiver-operating characteristic analysis. Cancer. 2004;102:259–68.
  50. Kim JH, Choi YD, Lee JS, Lee JH, Nam JH, Choi C. Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens. Gynecol Oncol. 2010;116:99–104.
  51. Dong SM, Kim HS, Rha SH, Sidransky D. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clin Cancer Res. 2001;7:1982–6.
  52. Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, et al. CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res. 2005;65:8961–7.
  53. Feng Q, Deftereos G, Hawes SE, Stern JE, Willner JB, Swisher EM, et al. DNA hypermethylation, Her-2/neu overexpression and p53 mutations in ovarian carcinoma. Gynecol Oncol. 2008;111:320–9.
  54. Kunze E, Wendt M, Schlott T. Promoter hypermethylation of the 14-3-3 sigma, SYK and CAGE-1 genes is related to the various phenotypes of urinary bladder carcinomas and associated with progression of transitional cell carcinomas. Int J Mol Med. 2006;18:547–57.
  55. Makos M, Nelkin BD, Reiter RE, Gnarra JR, Brooks J, Isaacs W, et al. Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors. Cancer Res. 1993;53:2719–22.
  56. Li Q, Jedlicka A, Ahuja N, Gibbons MC, Baylin SB, Burger PC, Issa JP. Concordant methylation of the ER and N33 genes in glioblastoma multiforme. Oncogene. 1998;16:3197–202.
  57. Zawlik I, Zakrzewska M, Witusik M, Golanska E, Kulczycka-Wojdala D, Szybka M, et al. KCTD11 expression in medulloblastoma is lower than in adult cerebellum and higher than in neural stem cells. Cancer Genet Cytogenet. 2006;170:24–8.
  58. Waha A, Koch A, Hartmann W, Mack H, Schramm J, Sorensen N, et al. Analysis of HIC-1 methylation and transcription in human ependymomas. Int J Cancer. 2004;110:542–9.
  59. Koul S, Houldsworth J, Mansukhani MM, Donadio A, McKiernan JM, Reuter VE, et al. Characteristic promoter hypermethylation signatures in male germ cell tumors. Mol Cancer. 2002;1:8.
  60. Rathi A, Virmani AK, Harada K, Timmons CF, Miyajima K, Hay RJ, et al. Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin Cancer Res. 2003;9:3674–8.
  61. Kanai Y, Ushijima S, Ochiai A, Eguchi K, Hui A, Hirohashi S. DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis. Cancer Lett. 1998;122:135–41.