Abstract
The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell differentiation is a potential new therapeutic approach for this devastating disease. ASCL1, a proneural transcription factor, plays a key role in normal brain development and is also expressed in a subset of GBM cells, but fails to engage a full differentiation programme in this context. Here, we investigated the barriers to ASCL1-driven differentiation in GBM stem cells. We see that ASCL1 is highly phosphorylated in GBM stem cells where its expression is compatible with cell proliferation. However, overexpression of a form of ASCL1 that cannot be phosphorylated on Serine–Proline sites drives GBM cells down a neuronal lineage and out of cell cycle more efficiently than its wild-type counterpart, an effect further enhanced by deletion of the inhibitor of differentiation ID2, indicating mechanisms to reverse the block to GBM cell differentiation.
Highlights
The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment
By comparing the activity of wild type (WT) and of a phospho-mutant form of ASCL1 that cannot be phosphorylated on SP consensus sites, we show that inhibition of ASCL1 phosphorylation increases the fraction of cells expressing neuronal markers and drives GBM cells to a post-mitotic neuronal-like state that is refractory to cell cycle re-entry upon growth factor stimulation
As we previously showed that proneural bHLH transcription factors can be highly phosphorylated on multiple SP sites by CDKs, and that multi-site phosphorylation restrains their pro-differentiation activity[28,29], we set out to test the effect of both wild type (WT) ASCL1 and a mutant version where all 5 SP sites are mutated to Alanine-Proline, 5S-A ASCL1 (Fig. S2C,D)
Summary
The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Given the resemblance of these cellular states to developmental intermediates, it is not surprising that developmental factors that regulate proliferation and differentiation of precursors in the embryonic brain are re-expressed in GBM12, especially in the PN subtype that contains a prevalence of OPC-like and NPC-like cellular states. One of these factors is the transcriptional regulator ASCL1, which belongs to the bHLH proneural family of proteins regulating neuronal differentiation in the e mbryo[13,14,15,16,17]. Proneural activity in GBM and explored the possibility that the oncogenic cell cycle environment may modulate ASCL1 phosphorylation, which in turn regulates its expression and activity
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