Abstract
Methylation of promoter DNA contributes to transcriptional silencing of various tumor-suppressor genes in cancer. Transcriptional silencing of 15-lipoxygenase-1 (15-LOX-1) promotes tumorigenesis. Methylation of 15-LOX-1 promoter DNA occurs in some cancers, but its mechanistic role in 15-LOX-1 transcriptional silencing is unclear. We examined the mechanistic role of 15-LOX-1 promoter DNA methylation in 15-LOX-1 transcriptional regulation in human colorectal cancers. 15-LOX-1 promoter methylation occurred in colorectal cancer cells in vitro, in 36% of tumor tissue samples of colorectal cancer patients, and in virtually no normal colonic mucosa samples of 50 human subjects with no history of colorectal cancer or polyps. 15-LOX-1 promoter DNA methylation levels, however, did not correlate with 15-LOX-1 expression levels (Spearman's r=0.21; P=0.38). We employed siRNA knockdown and genetic disruption models of DNA methyltransferases (DNMTs) to study the effects of this methylation on 15-LOX-1 expression in colon cancer cells. 15-LOX-1 promoter demethylation was insufficient to reestablish 15-LOX-1 expression. 15-LOX-1 transcription was activated by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) only after DNMT-1 dissociation from the 15-LOX-1 promoter and without altering 15-LOX-1 promoter DNA methylation. DNMT-1 protein hypomorphism impaired DNMT-1 recruitment to the 15-LOX-1 promoter, which allowed 15-LOX-1 transcription activation by SAHA. DNMT-1 has a direct suppressive role in 15-LOX-1 transcriptional silencing that is independent of 15-LOX-1 promoter DNA methylation.
Original language | English (US) |
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Pages (from-to) | 1981-1992 |
Number of pages | 12 |
Journal | FASEB Journal |
Volume | 22 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2008 |
Keywords
- Colon cancer
- DNMT-1 hypomorph protein
- Histone deacetylase inhibitor
- Transcriptional regulation
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
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