Skip to main content
SpringerLink
Log in

Signification of Hypermethylated in Cancer 1 (HIC1) as Tumor Suppressor Gene in Tumor Progression

  • Original Paper
  • Published:
Cancer Microenvironment

Abstract

Hypermethylated in cancer 1(HIC1) was identified as a strong suppressor gene in chromosome region 17p13.3 telomeric to TP53. This gene encodes a transcriptional repressor and is ubiquitously expressed in normal tissues but downexpressed in different tumor tissues where it is hypermethylated. The hypermethylation of this chromosomal region leads to epigenetic inactivation of HIC1, which would prompt cancer cells to alter survival and signaling pathways or specific transcription factors during the period of tumorigenesis. In vitro, HIC1 function is mainly a sequence-specific transcriptional repressor interacting with a still growing range of histone deacetylase(HDAC)-dependent and HDAC-independent corepressor complexes. Furthermore, a role for HIC1 in tumor development is firmly supported by Hic1 deficient mouse model and two double heterozygote models cooperate with p53 and Ptch1. Notably, our findings suggest that potential factors derived from tumor microenviroment may play a role in modulating HIC1 expression in tumor cells by epigenetic modification, which is responsible for tumor progression. In this review, we will describe genomic and proteinic structure of HIC1, and summary the potential role of HIC1 in human various solid tumors and leukemia, and explore the influence of tumor microenviroment on inducing HIC1 expression in tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wales MM et al (1995) p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med 1(6):570–577

    Article  PubMed  CAS  Google Scholar 

  2. Fleuriel C et al (2009) HIC1 (hypermethylated in cancer 1) epigenetic silencing in tumors. Int J Biochem Cell Biol 41(1):26–33

    Article  PubMed  CAS  Google Scholar 

  3. Jenal M, et al. (2010) Inactivation of the hypermethylated in cancer 1 tumour suppressor—not just a question of promoter hypermethylation? Swiss Med Wkly 140(w13106)

  4. Chen WY et al (2003) Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 33(2):197–202

    Article  PubMed  CAS  Google Scholar 

  5. Chen W et al (2004) Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Canc Cell 6(4):387–398

    Article  CAS  Google Scholar 

  6. Briggs KJ et al (2008) Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes Dev 22(6):770–785

    Article  PubMed  CAS  Google Scholar 

  7. Dehennaut V, Leprince D (2009) Implication of HIC1 (hypermethylated in cancer 1) in the DNA damage response. Bull Canc 96(11):E66–E72

    Google Scholar 

  8. Boulay G, et al. (2011) Loss of hypermethylated in cancer 1 (HIC1) in breast cancer cells contributes to stress induced migration and invasion through beta-2 adrenergic receptor (ADRB2) misregulation. J Biol Chem

  9. Foveau B, et al. (2012) Receptor tyrosyne kinase Epha2 is a direct target-gene of Hic1 (hypermethylated in cancer 1). J Biol Chem

  10. Carter MG et al (2000) Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Hum Mol Genet 9(3):413–419

    Article  PubMed  CAS  Google Scholar 

  11. Guerardel C et al (2001) 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 276(5):3078–3089

    Article  PubMed  CAS  Google Scholar 

  12. Pinte S et al (2004) Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1. Oncogene 23(22):4023–4031

    Article  PubMed  CAS  Google Scholar 

  13. Britschgi C et al (2006) Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. Oncogene 25(14):2030–2039

    Article  PubMed  CAS  Google Scholar 

  14. Mondal AM et al (2006) Identification and functional characterization of a novel unspliced transcript variant of HIC-1 in human cancer cells exposed to adverse growth conditions. Cancer Res 66(21):10466–10477

    Article  PubMed  CAS  Google Scholar 

  15. Albagli O et al (1995) The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. Cell Growth Differ 6(9):1193–1198

    PubMed  CAS  Google Scholar 

  16. Stogios PJ et al (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6(10):R82

    Article  PubMed  Google Scholar 

  17. Kelly KF, Daniel JM (2006) POZ for effect–POZ-ZF transcription factors in cancer and development. Trends Cell Biol 16(11):578–587

    Article  PubMed  CAS  Google Scholar 

  18. Pinte S et al (2004) 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 279(37):38313–38324

    Article  PubMed  CAS  Google Scholar 

  19. Ahmad KF et al (2003) Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol Cell 12(6):1551–1564

    Article  PubMed  CAS  Google Scholar 

  20. Ghetu AF et al (2008) Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell 29(3):384–391

    Article  PubMed  CAS  Google Scholar 

  21. Deltour S, Guerardel C, Leprince D (1999) 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 U S A 96(26):14831–14836

    Article  PubMed  CAS  Google Scholar 

  22. Chen WY et al (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123(3):437–448

    Article  PubMed  CAS  Google Scholar 

  23. Deltour S et al (1998) The carboxy-terminal end of the candidate tumor suppressor gene HIC-1 is phylogenetically conserved. Biochim Biophys Acta 1443(1–2):230–232

    PubMed  CAS  Google Scholar 

  24. Stankovic-Valentin N et al (2007) An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol Cell Biol 27(7):2661–2675

    Article  PubMed  CAS  Google Scholar 

  25. Bertrand S et al (2004) Identification and developmental expression of the zebrafish orthologue of the tumor suppressor gene HIC1. Biochim Biophys Acta 1678(1):57–66

    Article  PubMed  CAS  Google Scholar 

  26. Deltour S et al (2002) The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Mol Cell Biol 22(13):4890–4901

    Article  PubMed  CAS  Google Scholar 

  27. Chinnadurai G (2007) Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol 39(9):1593–1607

    Article  PubMed  CAS  Google Scholar 

  28. Shalizi A et al (2006) A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311(5763):1012–1017

    Article  PubMed  CAS  Google Scholar 

  29. Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8(12):947–956

    Article  PubMed  CAS  Google Scholar 

  30. Kanwal R, Gupta S (2011) Epigenetic modifications in cancer. Clin Genet

  31. Morton RA Jr et al (1996) Hypermethylation of chromosome 17P locus D17S5 in human prostate tissue. J Urol 156(2 Pt 1):512–516

    Article  PubMed  CAS  Google Scholar 

  32. Eguchi K et al (1997) DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history. Cancer Res 57(21):4913–4915

    PubMed  CAS  Google Scholar 

  33. Hayashi M et al (2001) Reduced HIC-1 gene expression in non-small cell lung cancer and its clinical significance. Anticancer Res 21(1B):535–540

    PubMed  CAS  Google Scholar 

  34. Fujii H et al (1998) Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Oncogene 16(16):2159–2164

    Article  PubMed  CAS  Google Scholar 

  35. Kanai Y et al (1998) DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis. Cancer Lett 122(1–2):135–141

    Article  PubMed  CAS  Google Scholar 

  36. Kanai Y et al (1999) DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology 29(3):703–709

    Article  PubMed  CAS  Google Scholar 

  37. Huang J et al (2000) High frequency allelic loss on chromosome 17p13.3-p11.1 in esophageal squamous cell carcinomas from a high incidence area in northern China. Carcinogenesis 21(11):2019–2026

    Article  PubMed  CAS  Google Scholar 

  38. Eads CA et al (2001) Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 61(8):3410–3418

    PubMed  CAS  Google Scholar 

  39. Koul S, et al. (2002) Characteristic promoter hypermethylation signatures in male germ cell tumors. Mol Cancer 1(8)

  40. Rood BR et al (2002) Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res 62(13):3794–3797

    PubMed  CAS  Google Scholar 

  41. Rathi A et al (2003) Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin Cancer Res 9(10 Pt 1):3674–3678

    PubMed  CAS  Google Scholar 

  42. Waha A et al (2003) Epigenetic silencing of the HIC-1 gene in human medulloblastomas. J Neuropathol Exp Neurol 62(11):1192–1201

    PubMed  CAS  Google Scholar 

  43. Waha A et al (2004) Analysis of HIC-1 methylation and transcription in human ependymomas. Int J Cancer 110(4):542–549

    Article  PubMed  CAS  Google Scholar 

  44. Nishida N et al (2008) Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology 47(3):908–918

    Article  PubMed  CAS  Google Scholar 

  45. Uhlmann K et al (2003) Distinct methylation profiles of glioma subtypes. Int J Cancer 106(1):52–59

    Article  PubMed  CAS  Google Scholar 

  46. Issa JP, Baylin SB, Herman JG (1997) DNA methylation changes in hematologic malignancies: biologic and clinical implications. Leukemia 11(Suppl 1):S7–S11

    PubMed  Google Scholar 

  47. Issa JP et al (1997) HIC1 hypermethylation is a late event in hematopoietic neoplasms. Cancer Res 57(9):1678–1681

    PubMed  CAS  Google Scholar 

  48. Huffman DM et al (2007) SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 67(14):6612–6618

    Article  PubMed  CAS  Google Scholar 

  49. Stocklein H et al (2008) 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 27(18):2613–2625

    Article  PubMed  CAS  Google Scholar 

  50. Tseng RC et al (2009) Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia 11(8):763–770

    PubMed  CAS  Google Scholar 

  51. Briones VR et al (2006) Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta. Biochem Biophys Res Commun 345(2):595–601

    Article  PubMed  CAS  Google Scholar 

  52. Zhang W et al (2010) A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene 29(17):2467–2476

    Article  PubMed  CAS  Google Scholar 

  53. Foveau B et al (2012) The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). J Biol Chem 287(8):5366–5378

    Article  PubMed  CAS  Google Scholar 

  54. Zhang B et al (2009) Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene 28(5):651–661

    Article  PubMed  Google Scholar 

  55. Jenal M et al (2009) The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1. Mol Canc Res 7(6):916–922

    Article  CAS  Google Scholar 

  56. Valenta T et al (2006) HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. EMBO J 25(11):2326–2337

    Article  PubMed  CAS  Google Scholar 

  57. Van Rechem C et al (2010) Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells. Mol Cell Biol 30(16):4045–4059

    Article  PubMed  Google Scholar 

  58. Pateras IS et al (2009) p57KIP2: Kipping the cell under control. Mol Canc Res 7(12):1902–1919

    Article  CAS  Google Scholar 

  59. Boulay G et al (2012) Loss of hypermethylated in cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through beta-2 adrenergic receptor (ADRB2) misregulation. J Biol Chem 287(8):5379–5389

    Article  PubMed  CAS  Google Scholar 

  60. Van Rechem C et al (2009) Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1). J Biol Chem 284(31):20927–20935

    Article  PubMed  Google Scholar 

  61. Di Marcotullio L et al (2004) REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A 101(29):10833–10838

    Article  PubMed  Google Scholar 

  62. Goodrich LV et al (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277(5329):1109–1113

    Article  PubMed  CAS  Google Scholar 

  63. Ferretti E et al (2005) Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med 11(12):537–545

    Article  PubMed  CAS  Google Scholar 

  64. Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61(2):513–516

    PubMed  CAS  Google Scholar 

  65. Spivakov M, Fisher AG (2007) Epigenetic signatures of stem-cell identity. Nat Rev Genet 8(4):263–271

    Article  PubMed  CAS  Google Scholar 

  66. Lee TI et al (2006) Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125(2):301–313

    Article  PubMed  CAS  Google Scholar 

  67. Widschwendter M et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39(2):157–158

    Article  PubMed  CAS  Google Scholar 

  68. Ohm JE et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39(2):237–242

    Article  PubMed  CAS  Google Scholar 

  69. Kalari S, Pfeifer GP (2010) Identification of driver and passenger DNA methylation in cancer by epigenomic analysis. Adv Genet 70(277–308)

    Google Scholar 

  70. Saito K et al (2008) Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy. Canc Sci 99(2):253–259

    Article  CAS  Google Scholar 

  71. Dumont N et al (2008) Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci U S A 105(39):14867–14872

    Article  PubMed  CAS  Google Scholar 

  72. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  PubMed  CAS  Google Scholar 

  73. Finak G et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527

    Article  PubMed  CAS  Google Scholar 

  74. Qiu W et al (2008) No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet 40(5):650–655

    Article  PubMed  CAS  Google Scholar 

  75. Hellebrekers DM et al (2007) Identification of epigenetically silenced genes in tumor endothelial cells. Cancer Res 67(9):4138–4148

    Article  PubMed  CAS  Google Scholar 

  76. Jing Y, et al. (2011) Epithelial-mesenchymal transition in tumor microenvironment. Cell Biosci 1(29)

  77. Xia D et al (2012) Prostaglandin E(2) promotes intestinal tumor growth via DNA methylation. Nat Med 18(2):224–226

    Article  PubMed  CAS  Google Scholar 

  78. Ng EK et al (2009) MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer. Br J Cancer 101(4):699–706

    Article  PubMed  CAS  Google Scholar 

  79. Claes B, Buysschaert I, Lambrechts D (2010) Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy. Heredity (Edinb) 105(1):152–160

    Article  CAS  Google Scholar 

  80. Lyko F, Brown R (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Canc Inst 97(20):1498–1506

    Article  CAS  Google Scholar 

  81. Zhou P, Lu Y, Sun XH (2012) Effects of a novel DNA methyltransferase inhibitor zebularine on human lens epithelial cells. Mol Vis 18(22–28)

    Google Scholar 

  82. Christman JK (2002) 5-azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21(35):5483–5495

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to the many authors whose excellent work we could not cite owing to space limitation. Research in the authors’ laboratory is supported by National Natural funding of China (81071747), National Basic Research Program of China (973 Program, 2011CB510106, and 2011CB504300), Shanghai Education Committee Key Discipline and Specialties Foundation Project Number: J50208, Program for Professor of Special Appointment (Eastern Scholar for J. W.),Shanghai Pujiang Program (10PJ1406400), Ph.D innovation fund from Shanghai Jiao Tong University School of Medicine (BXJ201103) and Shanghai Natural Science Foundation (11ZR1419600).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jianghua Zheng, Dan Xiong, Xueqing Sun, Jinglong Wang, Mingang Hao, Gang Xiao, Xiumin Wang & Jianhua Wang

  2. Department of Urological Surgery, Shanghai the Tenth People’s Hospital of Tong Ji University, Shanghai, 200072, China

    Tao Ding

  3. Shanghai Ruijin Hospital, Comprehensive Breast Health Center, Shanghai, 200025, China

    Yan Mao & Kunwei Shen

  4. Department of Thoracic Surgery, RenJi Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Yuejie Fu

Authors
  1. Jianghua Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueqing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinglong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingang Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tao Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiumin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuejie Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kunwei Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jianhua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianhua Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zheng, J., Xiong, D., Sun, X. et al. Signification of Hypermethylated in Cancer 1 (HIC1) as Tumor Suppressor Gene in Tumor Progression. Cancer Microenvironment 5, 285–293 (2012). https://doi.org/10.1007/s12307-012-0103-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12307-012-0103-1

Keywords

Search

Navigation