The effect of Bone Morphogenetic Proteins (BMPs) on glioblastoma propagation cells (GPCs) is being debated [1-5]. We observed that exposure of GPCs to BMP2/4 initiates a rapid proteasomal degradation of the pluripotency factor SOX2 followed by the differentiation of GPCs into glial cells using 5 primary human glioblastoma lines tested. Enforced expression of SOX2 in GPCs antagonized BMP2/4-induced gliogenesis and reduction of proliferation. Both outcomes are consistent with the role of SOX2 in normal neurogenesis [6-8]. Using gene expression analysis, we observed that level of SOX2 in different glioblastoma lines tracks with the levels of oncogenes H/K/N-RAS and OLIG2. Our work provides support for BMP2/4-SOX2 axis in GPCs and points to the proteasome-regulated degradation of SOX2 that initiates glycogenic differentiation similar to that observed during normal development [6, 7]. Our work supports a potential for developing novel therapeutic strategies aimed at differentiation of GPC into non-tumorigenic glia.