title: Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression.
abstract: PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc(Min) background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.
authors.affiliation: Biotech Research and Innovation Centre, Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: G G
authors.initials: GG
authors.lastname: Galli
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: H A
authors.initials: HA
authors.lastname: Multhaupt
authors.affiliation: Department of Clinical and Biological Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carrara
authors.affiliation: Biotech Research and Innovation Centre, Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K H
authors.initials: KH
authors.lastname: de Lichtenberg
authors.affiliation: The Finsen Laboratory, Faculty of Health Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: I B J
authors.initials: IB
authors.lastname: Christensen
authors.affiliation: Department of Pathology, Herlev Hospital, Herlev, Denmark.
authors.forename: D
authors.initials: D
authors.lastname: Linnemann
authors.affiliation: Department of Pathology, Diagnostic Center, Righospitalet, Copenhagen, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Santoni-Rugiu
authors.affiliation: Department of Clinical and Biological Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: R A
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Biotech Research and Innovation Centre, Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A H
authors.identifier: 0000000274073398
authors.initials: AH
authors.lastname: Lund
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; C575119:PRDM5 protein, mouse; D014157:Transcription Factors; D008994:Monoacylglycerol Lipases