Correction for Xu et al., BCL6 promotes glioma and serves as a therapeutic target

Significance Glioblastoma (GBM) is the most lethal brain malignancy lacking effective treatment. In this study, we demonstrate that BCL6 is a prognostic marker and a targetable GBM-promoting factor. Silencing of BCL6 inhibits the malignant phenotype of GBM cells and triggers cellular senescence. We also identify AXL as an important BCL6 transcriptional target, the expression of which is also regulated positively by NCoR, a BCL6 cofactor. Either silencing of BCL6 or targeted disruption of the BCL6/NCoR complex diminishes AXL expression and inhibits GBM growth. This study elucidates a crucial BCL6-mediated signaling pathway in GBM biology. More importantly, our results highlight the promise and merit of targeting BCL6 for treating this deadly disease. ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase–extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase–ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.