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Prdm5 suppresses ApcMin-driven intestinal adenomas and regulates monoacylglycerol lipase expression

Oncogene volume 33, pages 3342–3350 (2014)Cite this article

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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 ApcMin 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.

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Acknowledgements

We would like to acknowledge Julia Sidenius Johansen for her advice on TMA stainings, Bettina Mentz for excellent technical assistance and Fengqin Jia for mouse genotyping. This work was supported by the Danish National Research Foundation, the Danish National Advanced Technology Foundation, the Novo Nordisk Foundation, the EC FP7 programs (ONCOMIRS, grant agreement number 201102), the Lundbeck Foundation and the Danish Cancer Society.

Author information

Author notes

  1. G G Galli

    Present address: 7Current address: Stem Cell Program and Department of Hematology/Oncology, Children’s Hospital, Boston, MA 02115, USA.,

  2. G G Galli

    Present address: 8Current address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.,

Authors and Affiliations

  1. Biotech Research and Innovation Centre, Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark

    G G Galli, K H de Lichtenberg & A H Lund

  2. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    H A Multhaupt

  3. Department of Clinical and Biological Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy

    M Carrara & R A Calogero

  4. The Finsen Laboratory, Faculty of Health Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    I B J Christensen

  5. Department of Pathology, Herlev Hospital, Herlev, Denmark

    D Linnemann

  6. Department of Pathology, Diagnostic Center, Righospitalet, Copenhagen, Denmark

    E Santoni-Rugiu

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  1. G G Galli
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Correspondence to A H Lund.

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Galli, G., Multhaupt, H., Carrara, M. et al. Prdm5 suppresses ApcMin-driven intestinal adenomas and regulates monoacylglycerol lipase expression. Oncogene 33, 3342–3350 (2014). https://doi.org/10.1038/onc.2013.283

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