Abstract
Developmental transcription programs are epigenetically regulated by the competing actions of polycomb and trithorax (TrxG) protein complexes, which repress and activate genes, respectively. Ewing sarcoma is a developmental tumor that is associated with widespread de-regulation of developmental transcription programs, including HOX programs. Posterior HOXD genes are abnormally over-expressed by Ewing sarcoma and HOXD13, in particular, contributes to the tumorigenic phenotype. In MLL1 fusion-driven leukemia, aberrant activation of HOXA genes is epigenetically mediated by the TrxG complex and HOXA gene expression and leukemogenesis are critically dependent on the protein-protein interaction between the TrxG proteins MLL1 and menin. Based on these data, we investigated whether posterior HOXD gene activation and Ewing sarcoma tumorigenicity are similarly mediated by and dependent on MLL1 and/or menin. Our findings demonstrate that Ewing sarcomas express high levels of both MLL1 and menin and that continued expression of both proteins is required for maintenance of tumorigenicity. In addition, exposure of Ewing sarcoma cells to MI-503, an inhibitor of the MLL1-menin protein-protein interaction developed for MLL1-fusion driven leukemia, leads to loss of tumorigenicity and down-regulated expression of the posterior HOXD gene cluster. Together these data demonstrate an essential role for MLL1 and menin in mediating tumor maintenance and posterior HOXD gene activation in Ewing sarcoma. A critical dependency of these tumors on the MLL1-menin interaction presents a potentially novel therapeutic target.
Highlights
Normal embryogenesis and tissue maintenance are governed by the coordinated regulation of gene expression in the proper time and space
Our findings demonstrate that Ewing sarcomas express high levels of both MLL1 and menin and that continued expression of both proteins is required for maintenance of tumorigenicity
We and others have shown that the posterior HOXD genes, HOXD9, HOXD10, HOXD11, and HOXD13 are overexpressed by Ewing sarcoma [15, 35] and that the promoters of these genes are devoid of the repressive H3K27me3 mark and highly enriched with the MLL-mediated H3K4me3 mark [15, 21]
Summary
Normal embryogenesis and tissue maintenance are governed by the coordinated regulation of gene expression in the proper time and space. This process is directed by epigenetic modifications to chromatin that are mediated in part by the large, multi-subunit Polycomb (PcG) and Trithorax (TrxG) complexes [1]. PcG and TrxG proteins, which promote gene repression and activation, respectively, are highly expressed in stem cells and are key epigenetic mediators of both normal development and tumorigenesis [2]. Deregulation of developmental programs is evident in pediatric cancers, where the normal epigenetic processes governing stem cell self-renewal and differentiation are hijacked, promoting malignant transformation [3]. Reciprocal epigenetic regulation of HOX genes by www.impactjournals.com/oncotarget
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