Novel detection and differential utilization of a c-myc transcriptional block in colon cancer chemoprevention

Albert Einstein College of Medicine, New York, New York, United States
Cancer Research (Impact Factor: 9.33). 12/2002; 62(21):6006-10.
Source: PubMed


Mutations in the adenomatous polyposis coli (APC) gene, which initiate almost all human colon cancers, directly target the proto-oncogene, c-myc, by elevating beta-catenin/T-cell factor (TCF) signaling. We have shown that agents ascribed chemopreventive activity for colon cancer in fact also stimulate beta-catenin/TCF activity in vitro. Their effects on c-myc transcription were assayed using a novel variant of fluorescence in situ hybridization that detects c-myc transcription sites in intact nuclei. Increased transcriptional initiation of c-myc induced by the short-chain fatty acid, butyrate, consistent with elevated beta-catenin/TCF activity, was efficiently abrogated by a block to transcriptional elongation, resulting in decreased c-myc expression. 1alpha,25-Dihydroxyvitamin D(3) also induced transcriptional blockage. In contrast, the nonsteroidal anti-inflammatory drug, sulindac, increased c-myc expression, an effect attributable at least in part to its failure to induce transcriptional blockage. We have described a novel approach for evaluating the effects of chemopreventive agents on the expression of a gene critical in colonic tumorigenesis.

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    • "Chromatin compaction is associated with silencing of gene transcription and other functions of genome maintenance such as DNA replication and DNA damage response and repair (16–20). Deacetylation of histones represses the transcription of tumor suppressor genes such as the cyclin-dependent kinase inhibitor, p21 p21(WAF1/CIP1), and the DNA damage repair gene BRCA1, and directly or indirectly promotes the expression, activity, or downstream effects of known oncogenes such as c-MYC (21), RAS (22, 23), and AKT (24). Direct deacetylation of non-histone proteins p53, STAT3, c-MYC, α-tubulin, and Hsp90 is implicated in tumorigenesis (15, 25–27). "
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