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BCL6 promotes glioma and serves as a therapeutic target.

ABSTRACT: 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.

SUBMITTER: Xu L

PROVIDER: S-EPMC5393201 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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BCL6 promotes glioma and serves as a therapeutic target.

Xu Liang L Chen Ye Y Dutra-Clarke Marina M Mayakonda Anand A Hazawa Masaharu M Savinoff Steve E SE Doan Ngan N Said Jonathan W JW Yong William H WH Watkins Ashley A Yang Henry H Ding Ling-Wen LW Jiang Yan-Yi YY Tyner Jeffrey W JW Ching Jianhong J Kovalik Jean-Paul JP Madan Vikas V Chan Shing-Leng SL Müschen Markus M Breunig Joshua J JJ Lin De-Chen DC Koeffler H Phillip HP

Proceedings of the National Academy of Sciences of the United States of America 20170329 15

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 i ...[more]

PMID: 28356518

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BCL6 promotes glioma and serves as a therapeutic target.

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BCL6 promotes glioma and serves as a therapeutic target.

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