Investigation of PRDM12 locus role in colorectal adenocarcinoma cells

PRDM12 is not usually expressed in adult normal tissues; however, a pan-cancer meta-analysis based on The Cancer Genome Atlas (TCGA) reveals that the PRDM12 gene is upregulated in several cancer types. These data may suggest a putative oncogenic role for PRDM12. We decided to investigate the molecular and biological roles of PRDM12 in colorectal adenocarcinoma, where its expression seems more disrupted. First, we investigated its expression in colon carcinoma cell line (SW620, SW48) and found, with our surprise, that the PRDM12 gene is not transcribed from the canonical TSS due to the presence of a highly methylated CpG island before the promoter. PRDM12 transcriptional repression is so tight that neither inhibitors of DNA methylation (5-Azacytidine) PRC2-mediated histone methylation (EED226) nor histone deacetylation (Panobinostat), can restore its transcription. The only way we could succeed in re-expressing the gene was by forcing its transcription through a dCas9-VPR complex positioned nearby the putative TSS. Notwithstanding that, thorough analyses of the entire PRDM12 locus have, however, revealed the existence of another TSS located in the 3’UTR PRDM12 region. By modulating expression from this new putative promoter (dCas9-Krab-MeCP2 KD-system), we detected and characterized a new transcript in the “canonical” 3’UTR region. Interestingly, the transcript and the epigenetic marks (acetylation of H3K27) that are associated with the region suggest that the 3’UTR region of PRDM12 carries a new transcribed enhancer. Functional studies demonstrate that the enhancer up-regulates the expression of a nearby gene ABL1, a well-known oncogene. In conclusion our results show that PRDM12 is not per se involved in cancer development. However, the PRDM12 locus harbors a new transcribed enhancer in its 3’UTR that controls expression of the EXOSC2 and ABL1 genes. We propose that this 3’ UTR PRDM12 DNA element and not the PRDM12 product could be crucial for cancer arising and/or progression.