Abstract
Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL-Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non-tumor-initiating cells in glioblastoma.
Highlights
Epigenetic regulators play a pivotal role in the etiology of multiple malignancies
We identified a gene expression signature consisting of HOX genes in Glioblastoma neural stem (GNS) cells. (We hereby define the Homeobox-encoding genes in the clusters HOXA to HOXD as HOX genes, whereas we define the nonclustered, Homeobox-encoding genes found throughout the genome as Homeobox genes.) Interestingly, hierarchical clustering of GNS cells, neural stem (NS) cells, and cortical resections on the basis of expression of HOX genes alone segregated all samples into 2 main groups: 1 cluster populated by GNS cells and 1 including NS cells and non-neoplastic brain (Fig. 1A)
The epigenetic modifier mixed lineage leukemia (MLL) was detected at the protein level in all the GNS cells we examined, and at higher levels than in normal NS cells
Summary
Epigenetic regulators play a pivotal role in the etiology of multiple malignancies. The contribution of epigenetic factors to cellular heterogeneity in tumors has been poorly addressed and few mechanistic insights have been resolved, especially in human gliomas [6,7,8,9,10]. The role of epigenetic factors in subpopulations of cells that drive tumorigenesis has only been partially addressed, and studies of glioma have mostly focused on proteins belonging to the Polycomb group [11, 12]. The Trithorax group (TrxG) homolog mixed lineage leukemia (MLL) is an important epigenetic regulator during development and its role is especially well defined in hematopoiesis [13,14,15]. MLL is a histone methyltransferase that catalyzes the methylation of histone 3 at lysine 4 (H3K4; ref. 16), thereby inducing a complex series of epigenetic modifications that
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