title: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Marina
authors.initials: M
authors.lastname: Dutra-Clarke
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hazawa
authors.affiliation: Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Savinoff
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, and David Geffen School of Medicine, Los Angeles, CA 90095.
authors.forename: Ngan
authors.initials: N
authors.lastname: Doan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, and David Geffen School of Medicine, Los Angeles, CA 90095.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, and David Geffen School of Medicine, Los Angeles, CA 90095.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Ashley
authors.initials: A
authors.lastname: Watkins
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ding
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 169857, Singapore.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ching
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 169857, Singapore.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Kovalik
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Vikas
authors.initials: V
authors.lastname: Madan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Shing-Leng
authors.identifier: 0000-0002-3270-0525
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048; dchlin11@gmail.com Joshua.Breunig@cshs.org.|Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095.|Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Breunig
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; dchlin11@gmail.com Joshua.Breunig@cshs.org.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA 90048.
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA 90048.|National University Cancer Institute, National University Hospital, Singapore, 119074, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C084103:BCL6 protein, human; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D011799:Quinazolines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020794:Receptor Protein-Tyrosine Kinases; D020930:MAP Kinase Kinase Kinases; D000077156:Gefitinib; D000094963:Axl Receptor Tyrosine Kinase
keywords: AXL; BCL6; NCoR; ZBTB; glioblastoma multiforme