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BCL6 promotes glioma and serves as a therapeutic target. (Proc Natl Acad Sci U S A, Apr 2017)

Xu L1, Chen Y1, Dutra-Clarke M2, Mayakonda A1, Hazawa M1, Savinoff SE2, Doan N3, Said JW3, Yong WH3, Watkins A2, Yang H1, Ding LW1, Jiang YY1, Tyner JW4, Ching J5, Kovalik JP5, Madan V1, Chan SL1, Müschen M6, Breunig JJ7,8,9, Lin DC10,11, Koeffler HP1,11,12.

Author information
1 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
2 Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
3 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, and David Geffen School of Medicine, Los Angeles, CA 90095.
4 Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239.
5 Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 169857, Singapore.
6 Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
7 Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
8 Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095.
9 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
10 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore;
11 Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA 90048.
12 National University Cancer Institute, National University Hospital, Singapore, 119074, Singapore.

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.

KEYWORDS: AXL; BCL6; NCoR; ZBTB; glioblastoma multiforme

PMID: 28356518