Glioblastoma (GBM) contains rare glioma stem-like cells (GSCs) with capacities of self-renewal, multi-lineage differentiation, and resistance to conventional therapy. Drug-induced differentiation of GSCs is recognized as a promising approach of anti-glioma therapy. Accumulating evidence suggests that unique properties of stem cells depend on autophagy. Here we demonstrate that BIX01294, an inhibitor of a G9a histone methyltransferase (introducing H3K9me2 and H3K27me3 repressive marks) triggers autophagy in human glioma cells. Pharmacological or genetic inhibition of autophagy decreased LC3-II accumulation and GFP-LC3 punctation in BIX01294-treated cells. GSCs-enriched spheres originating from glioma cells and GBM patient-derived cultures express lower levels of autophagy related (ATG) genes than the parental glioma cell cultures. Typical differentiation inducers that upregulate neuronal and astrocytic markers in sphere cultures, increase the level of ATG mRNAs. G9a binds to the promoters of autophagy (LC3B, WIPI1) and differentiation-related (GFAP, TUBB3) genes in GSCs. Higher H3K4me3 (an activation mark) and lower H3K9me2 (the repressive mark) levels at the promoters of studied genes were detected in serum-differentiated cells than in sphere cultures. BIX01294 treatment upregulates the expression of autophagy and differentiation-related genes in GSCs. Pharmacological inhibition of autophagy decreases GFAP and TUBB3 expression in BIX01294-treated GSCs suggesting that BIX01294-induced differentiation of GSCs is autophagy-dependent.

AP-1 transcription factor known to playa role in cell proliferation and neuronal activation, it is also involved in apoptosis of cells in response to stress, DNA damaging agents or lack of survival signals. AP-l DNA binding complex is not a single transcritpion factor but a dimer consisting of members of Fos and Jun families. In this review, we discuss evidence that composition of the AP-1 complex is different under various physiological and pathophysiological conditions. Furthermore, we describe biochemical properties of Fos and Jun proteins that may explain the ability of this transcription factor to activate different sets of genes in response to different stimuli. We propose a hypothesis that AP-1 might contribute to distinct biological processes because an activation of specific signaling pathways results in changes of AP-1 composition and/or phosphorylation status and modulates its transactivating potential towards different promoters.