Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer.
HMGCS2, the gene that regulates ketone body production, is expressed in liver and several extrahepatic tissues, such as the colon. In CaCo-2 colonic epithelial cells, the expression of this gene increases with cell differentiation. Accordingly, immunohistochemistry with specific antibodies shows that HMGCS2 is expressed mainly in differentiated cells of human colonic epithelium. Here, we used a chromatin immunoprecipitation assay to study the molecular mechanism responsible for this expression pattern. The assay revealed that HMGCS2 is a direct target of c-Myc, which represses HMGCS2 transcriptional activity. c-Myc transrepression is mediated by blockade of the transactivating activity of Miz-1, which occurs mainly through a Sp1-binding site in the proximal promoter of the gene. Accordingly, the expression of human HMGCS2 is down-regulated in 90% of Myc-dependent colon and rectum tumors. HMGCS2 protein expression is down-regulated preferentially in moderately and poorly differentiated carcinomas. In addition, it is also down-regulated in 80% of small intestine Myc-independent tumors. Based on these findings, we propose that ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2.
Camarero
Nuria
N
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
Mascaró
Cristina
C
Mayordomo
Cristina
C
Vilardell
Felip
F
Haro
Diego
D
Marrero
Pedro F
PF
D000107:Acetylation; D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D004848:Epithelium / Q000473:pathology; D016259:Genes, myc; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D007657:Ketone Bodies / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D006657:Histones; D007657:Ketone Bodies; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C107961:ZBTB17 protein, human; D006904:Hydroxymethylglutaryl-CoA Synthase; D006655:Histone Deacetylases