BCL6 promotes glioma and serves as a therapeutic target

Liang Xu, Ye Chen, Marina Dutra-Clarke, Anand Mayakonda, Masaharu Hazawa, Steve E. Savinoff, Ngan Doan, Jonathan W. Said, William H. Yong, Ashley Watkins, Henry Yang, Ling Wen Ding, Yan Yi Jiang, Jeffrey W. Tyner, Jianhong Ching, Jean Paul Kovalik, Vikas Madan, Shing Leng Chan, Markus Müschen, Joshua J. BreunigDe Chen Lin, H. Phillip Koeffler, Webster K. Cavenee

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 ty-rosine 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 antipro-liferative 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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number15
DOIs
StatePublished - 2017

Keywords

  • AXL
  • BCL6
  • Glioblastoma multiforme
  • NCoR
  • ZBTB

ASJC Scopus subject areas

  • General

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