RBPJ maintains brain tumor–initiating cells through CDK9-mediated transcriptional elongation

γ-Secretase inhibitor–resistant glioblastoma stem cells require RBPJ to propagate

“…Although no stratified clinical trial to assess GSI for the treatment of proneural GBMs has been carried out, identification of the molecular mechanism of GSI resistance in GBM has the potential to help develop novel therapies for this deadly disease. In the current issue, Xie et al elegantly demonstrate that a mediator of Notch signaling, RBPJ, is overexpressed in GSI-resistant BTICs preferentially in proneural GBMs and is required for BTIC propagation both in vitro and in vivo (25). The results of this study are of substantial clinical relevance, because a mechanism of GSI resistance in BTICs has been identified, thereby providing a new approach to target GSI-resistant tumor cells in general.…”

“…Indeed, loss of RBPJ has been shown to induce expression of several Notch target genes, either in the presence or absence of NICD, and increase tumorigenesis in breast cancer and Burkitt lymphoma cells (37). In contrast, Xie et al show that knockdown of RBPJ only derepresses a few Notch target genes, such as HES5, but induces apoptosis in BTICs (25). One possible reason for these opposite effects from knockdown of RBPJ in tumor cells is that the breast cancer cells and Burkitt lymphoma cells used were dependent on Notch signaling to grow (37), whereas the BTICs used by Xie et al were already independent of Notch signaling for their growth (GSI-resistant cells) (Figure 1).…”

“…Xie et al performed RNA-seq to examine changes in the transcriptional profile of BTICs in response to RBPJ knockdown or Notch signaling blockade with GSI (25). Only 10% to 15% of genes were commonly regulated by both RBPJ and Notch signaling, suggesting that RBPJ regulates BTIC propagation mostly through the regulation of Notch-independent genes, an observation supported by the fact that propagation of GSI-treated BTICs is independent of Notch signaling.…”

“…Only 10% to 15% of genes were commonly regulated by both RBPJ and Notch signaling, suggesting that RBPJ regulates BTIC propagation mostly through the regulation of Notch-independent genes, an observation supported by the fact that propagation of GSI-treated BTICs is independent of Notch signaling. Xie et al determined that tumorigenesis-associated genes FOXM1, CCNA2 (cyclin A2), and KRAS are not only exclusively regulated by RBPJ at the transcriptional level but also contain RBPJ binding sites at their promoter regions, suggesting that these genes are possible direct targets of RBPJ in BTICs (25 Figure 1). In addition, knockdown of RBPJ expression by shRNA decreased BTIC propagation in vitro and in vivo by inducing apoptosis (25).…”

“…Xie et al determined that tumorigenesis-associated genes FOXM1, CCNA2 (cyclin A2), and KRAS are not only exclusively regulated by RBPJ at the transcriptional level but also contain RBPJ binding sites at their promoter regions, suggesting that these genes are possible direct targets of RBPJ in BTICs (25 Figure 1). In addition, knockdown of RBPJ expression by shRNA decreased BTIC propagation in vitro and in vivo by inducing apoptosis (25). This reduction in BTIC propagation prolonged survival in mice bearing intracranial xenografts (25).…”