Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various sources and induced into different cell types. Although MSCs possess immune privilege and are more easily obtained, their propensity to tumorigenesis and immune responses they might bring to patients have not been fully explored. Epigenomic revolution like changes in DNA methylation and chromatin modification have been hypothesized to be critical in the determination of lineage-specific differentiation and tumorigenesis of MSCs but has not been forwardly proved. We identified the Polycomb group-governed loci in MSCs and tracked their differential methylation changes during the MSC-to-liver or MSC-to-adipocyte differentiation. These loci were also differentially methylated in breast cancer (n=93) and liver cancer (n=40). In an independent collection of liver cancer (n=100), the methylation states of these Polycomb-governed loci like Trip10, Casp8AP2, ENSA and ZNF484 were clustered together in contrast to the non-Polycomb targets like HIC1 and RassF1A. We then developed and applied a targeted DNA methylation method to methylate the Polycomb group protein-governed gene, Trip10, in MSCs which accelerated the cell fate determination of MSCs. Targeted methylation of Casp8AP2, another Polycomb group protein-governed gene, increased cellular survival and its resistance to drugs. The targeted methylation of ENSA and ZNF484 reveal the epigenomic evolution. Targeted methylation of HIC1 and RassF1A, both are tumor suppressors but not the Polycomb target genes, transformed MSCs into tumor stem cell-like cells. With this new method, we proved that DNA methylation within critical loci is sufficient to steer the cell fate of MSCs. (Supported in part by NSC 100-2320-B-194-001)

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 3130. doi:1538-7445.AM2012-3130