Abstract 1051: UHRF1 is highly expressed in childhood liver tumors and interacts with DNMT1 and USP7 to guide tumor suppressor gene silencing
2012
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL
Embryonal tumors are thought to arise from immature tissue during intrauterine or early postnatal development and display apart from specific genetic changes in developmental signaling pathways a relatively normal genomic background. Instead, epigenetic events appear to be involved in key steps of the earliest phases of neoplastic evolution. However, the mechanistic basis responsible for epigenetic alterations in these early-onset tumors and the role of the DNA methylation machinery therein is still not known. In order to define the impact of epigenetic factors in embryonal tumor development we made use of hepatoblastoma (HB), the most common liver tumor of early childhood, as a model for a pristine and genetically “clean” tumor. In this study we identified ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to be highly overexpressed in HB tumors compared to normal liver tissue, a protein known to preferentially bind to hemi-methylated DNA. Using immunoprecipitation, we furthermore show that UHRF1 binds in concert with DNA methyltransferase 1 (DNMT1) and ubiquitin specific peptidase 7 (USP7) as a trimeric complex to promoter regions of tumor suppressor genes relevant in HB, such as hedgehog interacting protein (HHIP), insulin-like growth factor binding protein 3 (IGFBP3), and secreted frizzled-related protein 1 (SFRP1). These genes are epigenetically silenced in HB, as evidenced by heavy DNA methylation and enrichment of the repressive H4K27me3 chromatin mark. Interestingly, knockdown of UHRF1 expression via RNA interference resulted in promoter demethylation and a shift towards the active H3K4me2 chromatin mark of the three tumor suppressor genes. Altogether, these data suggest that aberrant expression of the epigenetic regulator UHRF1 and excessive binding of a trimeric complex consisting of UHRF1/DNMT1/USP7 results in silencing of tumor suppressor genes in HB and may display an important mechanism in the initial phases of embryonal tumorigenesis in general.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1051. doi:1538-7445.AM2012-1051
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