Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors

Abstract

To clarify the role of DNA methylation in the silencing of the expression of cyclin-dependent kinase inhibitor p57KIP2 seen in certain tumors, we investigated the methylation status of its 5′ CpG island in various tumor cell lines and primary cancers. Dense methylation of the region around the transcription start site was detected in 1 out of 10 colorectal, 2 out of 8 gastric, and 6 out of 14 hematopoietic tumor cell lines and in 5 out of 35 (14%) gastric, 6 out of 20 (30%) hepatocellular, and 2 out of 18 (11%) pancreatic cancers; 7 out of 25 (28%) acute myeloid leukemia cases also showed methylation of the p57KIP2 gene, which strongly correlated with the CpG island methylator phenotype (P<0.001). Detailed mapping revealed that dense methylation of the region around the transcription start site (−300 to +400), but not of the edges of the CpG island, was closely associated with gene silencing. 5-aza-2′-deoxycytidine, a methyltransferase inhibitor, restored expression of p57KIP2, and chromatin immunoprecipitation using anti-histone H3 and H4 antibodies showed histone to be deacetylated in cell lines where p57KIP2 was methylated at the transcription start site. Regional methylation and histone deacetylation thus appear to be crucially involved in the silencing of p57KIP2 expression in human tumors.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

CDK:

cyclin dependent kinase

RT–PCR:

reverse transcriptase PCR

TSA:

trichostatin A

HDAC:

histone deacetylase

CIMP:

CpG island methylator phenotype

References

  • Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG . 2001 Hum. Mol. Genet. 10: 687–692

  • Bepler G, Garcia-Blanco MA . 1994 Proc. Natl. Acad. Sci. USA 91: 5513–5517

  • Bird A . 2002 Genes Dev. 16: 6–21

  • Bird AP, Wolffe AP . 1999 Cell 99: 451–454

  • Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB . 1999a Nat. Genet. 21: 103–107

  • Cameron EE, Baylin SB, Herman JG . 1999b Blood 94: 2445–2451

  • Chung WY, Yuan L, Feng L, Hensle T, Tycko B . 1996 Hum. Mol. Genet. 5: 1101–1108

  • Clark SJ, Harrison J, Paul CL, Frommer M . 1994 Nucleic Acids Res. 22: 2990–2997

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Elledge SJ . 1996 Science 274: 1664–1672

  • Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG . 2000 J. Natl. Cancer Inst. 92: 564–569

  • Fujita N, Shimotake N, Ohki I, Chiba T, Saya H, Shirakawa M, Nakao M . 2000 Mol. Cell. Biol. 20: 5107–5118

  • Hatada I, Mukai T . 1995 Nat. Genet. 11: 204–206

  • Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, Nakayama M, Niikawa N, Mukai T . 1996 Nat. Genet. 14: 171–173

  • Herman JG, Jen J, Merlo A, Baylin SB . 1996 Cancer Res. 56: 722–727

  • Issa JP . 2000 Curr. Top. Microbiol. Immunol. 249: 101–118

  • Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovszki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R . 2001 Nat. Genet. 27: 31–39

  • Jones PA . 1999 Trends Genet. 15: 34–37

  • Jones PA, Laird PW . 1999 Nat. Genet. 21: 163–167

  • Krskova-Honzatkova L, Cermak J, Sajdova J, Stary J, Sedlacek P, Sieglova Z . 2001 Leuk. Res. 25: 45–53

  • Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M . 1997 Nat. Med. 3: 231–234

  • Matsumoto M, Furihata M, Ohtsuki Y, Sasaguri S, Ogoshi S . 2000 Anticancer Res. 20: 1947–1952

  • Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ . 1995 Genes Dev. 9: 650–662

  • Matsuoka S, Thompson JS, Edwards MC, Bartletta JM, Grundy P, Kalikin LM, Harper JW, Elledge SJ, Feinberg AP . 1996 Proc. Natl. Acad. Sci. USA 93: 3026–3030

  • Mummaneni P, Yates P, Simpson J, Rose J, Turker MS . 1998 Nucleic Acids Res. 26: 5163–5169

  • Ng HH, Jeppesen P, Bird A . 2000 Mol. Cell. Biol. 20: 1394–1406

  • Oya M, Schulz WA . 2000 Br. J. Cancer 83: 626–631

  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M . 1995 Science 269: 682–685

  • Salem CE, Markl ID, Bender CM, Gonzales FA, Jones PA, Liang G . 2000 Int. J. Cancer 87: 179–185

  • Schwienbacher C, Gramantieri L, Scelfo R, Veronese A, Calin GA, Bolondi L, Croce CM, Barbanti-Brodano G, Negrini M . 2000 Proc. Natl. Acad. Sci. USA 97: 5445–5449

  • Sherr CJ . 2000 Cancer Res. 60: 3689–3695

  • Sheu JC, Lin YW, Chou HC, Huang GT, Lee HS, Lin YH, Huang SY, Chen CH, Wang JT, Lee PH, Lin JT, Lu FJ, Chen DS . 1999 Br. J. Cancer 80: 468–476

  • Shin JY, Kim HS, Lee KS, Kim J, Park JB, Won MH, Chae SW, Choi YH, Choi KC, Park YE, Lee JY . 2000a Exp. Mol. Med. 32: 79–83

  • Shin JY, Kim HS, Park J, Park JB, Lee JY . 2000b Cancer Res. 60: 262–265

  • Tokino T, Urano T, Furuhata T, Matsushima M, Miyatsu T, Sasaki S, Nakamura Y . 1996 Hum. Genet. 97: 625–631

  • Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . 1999a Proc. Natl. Acad. Sci. USA 96: 8681–8686

  • Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB, Issa JP . 1999b Cancer Res. 59: 5438–5442

  • Toyota M, Ho C, Ohe-Toyota M, Baylin SB, Issa JP . 1999c Cancer Res. 59: 4535–4541

  • Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP . 2001 Blood 97: 2823–2829

  • Toyota M, Shen L, Ohe-Toyota M, Hamilton SR, Sinicrope FA, Issa JP . 2000 Cancer Res. 60: 4044–4048

  • Tycko B . 2000 J. Clin. Invest. 105: 401–407

  • Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M . 2000 Cancer Res. 60: 1835–1839

  • Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y . 1998 Proc. Natl. Acad. Sci. USA 95: 1392–1397

  • Winqvist R, Mannermaa A, Alavaikko M, Blanco G, Taskinen PJ, Kiviniemi H, Newsham I, Cavenee W . 1993 Cancer Res. 53: 4486–4488

  • Wong DJ, Foster SA, Galloway DA, Reid BJ . 1999 Mol. Cell. Biol. 19: 5642–5651

  • Xiong Z, Laird PW . 1997 Nucleic Acids Res. 25: 2532–2534

  • Yan Y, Frisen J, Lee MH, Massague J, Barbacid M . 1997 Genes Dev. 11: 973–983

  • Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ . 1997 Nature 387: 151–158

Download references

Acknowledgements

This study is supported by the Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Eduction, Culture, Sport, Science, and Technology (M Toyota, F Itoh, T Tokino and K Imai). T Kikuchi is a research fellow from the Japanese Society for the Promotion of Science. H Suzuki is a postdoctoral fellow from the Japanese Society for the Promotion of Science. The authors thank Dr William F Goldman for editing the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Minoru Toyota.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kikuchi, T., Toyota, M., Itoh, F. et al. Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors. Oncogene 21, 2741–2749 (2002). https://doi.org/10.1038/sj.onc.1205376

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205376

Keywords

This article is cited by

Search

Quick links