Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers

Ajay Goel, Christian N. Arnold, Pierfrancesco Tassone, Dong K. Chang, Donna Niedwiecki, Jeannette M. Dowell, Linda Wasserman, Carolyn Compton, Robert J. Mayer, Monica M. Bertagnolli, C. Richard Boland

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Runt domain transcription factors are important targets of TGF-β super-family proteins and play a crucial role in mammalian development. Three mammalian runt-related genes, RUNXI, RUNX2 and RUNX3, have been described. RUNX3 has been shown to be a putative tumor suppressor gene localized to chromosome Ip36, a region showing frequent loss of heterozygosity events in colon, gastric, breast and ovarian cancers. Because of the important role of TGF-β signaling in the human colon, we hypothesized that RUNX3 may serve as a key tumor suppressor in human colon cancers and colon cancer-derived cell lines. We examined RUNX3 expression and the frequency of RUNX3 promoter hypermethylation in 17 colon cancer cell lines and 91 sporadic colorectal cancers. Semiquantitative analysis of RUNX3 transcripts was performed by RT-PCR and de novo methylation of the RUNX3 promoter was studied by a methylation-specific PCR (MSP) assay. Nineteen of 91 informative tumors (21%) and Il of 17 (65%) colon cancer cell lines exhibited hypermethylation of the RUNX3 promoter. Interestingly, RUNX3 promoter hypermethylation was more common in tumors exhibiting high frequency of microsatellite instability (MSI-H) (33% of MSI-H vs. 12% of MSI-L/MSS tumors; p = 0.012). Hypermethylation of the RUNX3 promoter correlated with loss of mRNA transcripts in all cell lines. RUNX3 promoter methylation was reversed and its expression restored in SW48 and HCT15 colon cancer cells after treatment with the demethylating agent 5-aza-2′- deoxycytidine, indicating that loss of expression is caused by epigenetic inactivation in colon carcinogenesis. This is the first demonstration of frequent de novo hypermethylation of the RUNX3 promoter in sporadic colon cancers. The significant association of RUNX3 promoter hypermethylation with MSI-H colon cancers suggests that RUNX3 is a novel target of methylation, along with the hMLHI gene, in the evolution of MSI-H colorectal cancers.

Original languageEnglish (US)
Pages (from-to)754-759
Number of pages6
JournalInternational Journal of Cancer
Volume112
Issue number5
DOIs
StatePublished - Dec 10 2004
Externally publishedYes

Fingerprint

Epigenomics
Microsatellite Repeats
Colonic Neoplasms
Methylation
Cell Line
decitabine
Core Binding Factor alpha Subunits
Colorectal Neoplasms
Neoplasms
Colon
Polymerase Chain Reaction
Microsatellite Instability
Loss of Heterozygosity
Tumor Suppressor Genes
Ovarian Neoplasms
Genes
Stomach Neoplasms
Carcinogenesis
Transcription Factors
Chromosomes

Keywords

  • Colon cancer
  • Methylation
  • RUNX3

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Goel, A., Arnold, C. N., Tassone, P., Chang, D. K., Niedwiecki, D., Dowell, J. M., ... Boland, C. R. (2004). Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. International Journal of Cancer, 112(5), 754-759. https://doi.org/10.1002/ijc.20472

Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. / Goel, Ajay; Arnold, Christian N.; Tassone, Pierfrancesco; Chang, Dong K.; Niedwiecki, Donna; Dowell, Jeannette M.; Wasserman, Linda; Compton, Carolyn; Mayer, Robert J.; Bertagnolli, Monica M.; Boland, C. Richard.

In: International Journal of Cancer, Vol. 112, No. 5, 10.12.2004, p. 754-759.

Research output: Contribution to journalArticle

Goel, A, Arnold, CN, Tassone, P, Chang, DK, Niedwiecki, D, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM & Boland, CR 2004, 'Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers', International Journal of Cancer, vol. 112, no. 5, pp. 754-759. https://doi.org/10.1002/ijc.20472
Goel A, Arnold CN, Tassone P, Chang DK, Niedwiecki D, Dowell JM et al. Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. International Journal of Cancer. 2004 Dec 10;112(5):754-759. https://doi.org/10.1002/ijc.20472
Goel, Ajay ; Arnold, Christian N. ; Tassone, Pierfrancesco ; Chang, Dong K. ; Niedwiecki, Donna ; Dowell, Jeannette M. ; Wasserman, Linda ; Compton, Carolyn ; Mayer, Robert J. ; Bertagnolli, Monica M. ; Boland, C. Richard. / Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. In: International Journal of Cancer. 2004 ; Vol. 112, No. 5. pp. 754-759.
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