Novel detection and differential utilization of a c-myc transcriptional block in colon cancer chemoprevention.
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.
Wilson
Andrew J
AJ
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467, USA. awilson@montefiore.org
Velcich
Anna
A
Arango
Diego
D
Kurland
Amy R
AR
Shenoy
Shailesh M
SM
Pezo
Rossanna C
RC
Levsky
Jeffrey M
JM
Singer
Robert H
RH
Augenlicht
Leonard H
LH
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D015342:DNA Probes; D004100:Dihydroxycholecalciferols / Q000494:pharmacology; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D016588:Anticarcinogenic Agents; D002087:Butyrates; D015342:DNA Probes; D004100:Dihydroxycholecalciferols; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D013467:Sulindac; C023850:1 alpha,24-dihydroxyvitamin D3