Abstract
Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults. Although the stem-like properties of GICs, such as self-renewal and tumorigenicity, are epigenetically regulated, the role of a major chromatin remodeling complex in human, the SWI/SNF complex, remains unknown in these cells. We here demonstrate that the SWI/SNF core complex, that is associated with a unique corepressor complex through the d4-family proteins, DPF1 or DPF3a, plays essential roles in stemness maintenance in GICs. The serum-induced differentiation of GICs downregulated the endogenous expression of DPF1 and DPF3a, and the shRNA-mediated knockdown of each gene reduced both sphere-forming ability and tumor-forming activity in a mouse xenograft model. Rescue experiments revealed that DPF1 has dominant effects over DPF3a. Notably, whereas we have previously reported that d4-family members can function as adaptor proteins between the SWI/SNF complex and NF-κB dimers, this does not significantly contribute to maintaining the stemness properties of GICs. Instead, these proteins were found to link a corepressor complex containing the nuclear receptor, TLX, and LSD1/RCOR2 with the SWI/SNF core complex. Collectively, our results indicate that DPF1 and DPF3a are potential therapeutic targets for glioblastoma.
Highlights
Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults
By Quantitative real-time room temperature (RT)-PCR (qRT-PCR) and western blotting using our glioma initiating cells (GICs) preparations, we checked the expression of the POU3F2, SOX2, SALL2 and OLIG2, which have been reported to be required for the reconstitution and maintenance of stemness[6] (Fig. 1a, and Supplementary Fig. S1)
By comparing the RNA and protein levels between the sphere and differentiated monolayer GIC cultures, we found that all 4 transcription factors were at higher levels in sphere culture, indicating that these GIC cultures had very similar properties to stem-like tumor propagating cells (TPCs) reported previously[6]
Summary
Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults. We here demonstrate that the SWI/SNF core complex, that is associated with a unique corepressor complex through the d4-family proteins, DPF1 or DPF3a, plays essential roles in stemness maintenance in GICs. The seruminduced differentiation of GICs downregulated the endogenous expression of DPF1 and DPF3a, and the shRNA-mediated knockdown of each gene reduced both sphere-forming ability and tumor-forming activity in a mouse xenograft model. Using gene expression data from both stem-like and differentiated cell populations, it was shown that the simultaneous expression of four core transcription factors, POU3F2, SALL2, SOX2 and OLIG2, can reprogram differentiated GBM cells into spherogenic stem-like tumor-propagating cells[6] These results demonstrate a plastic developmental hierarchy in GBM cell populations and reveal essential roles of epigenetic regulation in these biological processes[7]. We demonstrated from our analysis in 293FT cells that DPF3a and 3b are the most effective cofactors of the SWI/SNF complex for RelA/p50 activation
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