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.

  • Short Communication
  • Published:

Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer

Abstract

Tumor suppressor p53 is known to play a crucial role in chemosensitivity in colorectal cancer. We previously demonstrated that an apoptosis-associated speck-like protein, ASC, is a p53-target gene which regulates p53-Bax mitochondrial apoptotic pathway. ASC is also known to be a target of methylation-induced gene silencing. An inactivation of ASC might thus cause resistance to chemotherapy, and if this is the case, then the expression of ASC would restore the chemosensitivity. The aim of this study was to clarify this hypothesis. ASC was methylated in 25% of all resected specimens in patients with colorectal cancer; however, ASC methylation did not always correspond to a lack of ASC protein. When expressed in colon cancer cells, in which ASC is absent due to methylation, ASC was found to enhance the chemosensitivity in a p53-dependent manner. In p53-null cells, ASC increased the p53-mediated cell death induced by p53-expressing adenovirus infection. Our data suggest that the methylation-induced silencing of ASC might cause resistance to p53-mediated chemosensitivity in colorectal cancer. The gene introduction of ASC may thus restore such chemosensitivity, and this modality may therefore be a useful new treatment strategy for colorectal cancer.

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

Similar content being viewed by others

References

  • Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L et al. (1999). J Clin Invest 104: 263–269.

  • Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM . (2000). Cancer Res 60: 6236–6242.

  • Hwang PM, Bunz F, Yu J, Rago C, Chan TA, Murphy MP et al. (2001). Nat Med 7: 1111–1117.

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. (1993). Cell 75: 817–825.

  • Green DR, Reed JC . (1999). Science 281: 1309–1312.

  • Guan X, Sagara J, Yokoyama T, Koganehira Y, Oguchi M, Saida T et al. (2003). Int J Cancer 107: 202–208.

  • Herman JG, Graff R, Myohanen S, Nelkin BD, Baylin SB . (1996). Proc Natl Acad Sci 93: 9821–9826.

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . (1991). Science 253: 49–53.

  • Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE et al. (1994). Science 266: 807–810.

  • Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP et al. (2004). Nature 430: 213–218.

  • Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N et al. (1999). J Biol Chem 274: 33835–33838.

  • Miyashita T, Reed JC . (1995). Cell 80: 293–298.

  • Moriai R, Tsuji N, Kobayashi D, Yagihashi A, Namiki Y, Takahashi H et al. (2002). Anticancer Res 22: 4163–4168.

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. (2000). Science 288: 1053–1058.

  • Ohtsuka T, Ryu H, Minamishima YA, Macip S, Sagara J, Nakayama KI et al. (2004). Nat Cell Biol 6: 121–128.

  • Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C et al. (1993). Am J Pathol 142: 1534–1543.

  • Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, Sagara J et al. (2002). J Exp Med 196: 1605–1615.

  • Vogelstein B, Lane D, Levine AJ . (2000). Nature 408: 307–310.

  • Yokoyama T, Sagara J, Guan X, Masumoto J, Takeoka M, Komiyama Y et al. (2003). Cancer Lett 202: 101–108.

  • Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L . (2003). Proc Natl Acad Sci USA 100: 1931–1936.

  • Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B . (2000). Science 290: 989–992.

Download references

Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry for Education, Science, Sports, and Culture of Japan (No. 16790780), and the National Institutes of Health (CA078356-05; CA80058-06).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T Ohtsuka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohtsuka, T., Liu, XF., Koga, Y. et al. Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer. Oncogene 25, 1807–1811 (2006). https://doi.org/10.1038/sj.onc.1209204

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209204

Keywords

This article is cited by

Search

Quick links