Prdm5 suppresses ApcMin-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.

Genomic and Proteomic Analyses of Prdm5 Reveal Interactions with Insulator Binding Proteins in Embryonic Stem Cells

“…Functionally, PRDM5 has been coined a tumor suppressor, as the promoter is frequently found methylated in different cancer types (14)(15)(16)(17); however, genetic evidence causally establishing tumor-suppressive functions of PRDM5 has been published only recently (60), and the Prdm5 gene trap mouse strain employed in this study does not develop spontaneous tumors (19). However, while Prdm5 gene trap animals are viable and fertile (19), morpholino experiments in zebrafish embryos revealed an essential role for Prdm5 (18).…”

MicroRNA-21 regulates prostaglandin E2 signaling pathway by targeting 15-hydroxyprostaglandin dehydrogenase in tongue squamous cell carcinoma

“…Deregulations of miR-21 and miR-130b, as well as deregulation of GPD1L, HLF, HPGD and MGLL have been reported either in HNOC or other cancer types [15, 16, 36–42], and these MRMs represent significant functional relevance in OTSCC. GPD1L has the glycerol-3-phosphate dehydrogenase enzyme activity and is a regulator of HIF-1α stability [40].…”

Loss of PRDM11 promotes MYC-driven lymphomagenesis

“…[6][7][8][9] Furthermore, a number of PRDMs exhibit tumor suppression functions: for example, PRDM1 is a tumor suppressor of diffuse large B-cell lymphomas (DLBCLs), 10,11 whereas PRDM5 is a tumor suppressor of gastrointestinal carcinogenesis. 12,13 One of the most well-characterized proto-oncogenes is the transcription factor MYC, which is deregulated in various cancers, including non-Hodgkin lymphomas.…”