@article{5853163438e743b8bc35a18a95e30b7e,
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 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.",
keywords = "AXL, BCL6, Glioblastoma multiforme, NCoR, ZBTB",
author = "Liang Xu and Ye Chen and Marina Dutra-Clarke and Anand Mayakonda and Masaharu Hazawa and Savinoff, {Steve E.} and Ngan Doan and Said, {Jonathan W.} and Yong, {William H.} and Ashley Watkins and Henry Yang and Ding, {Ling Wen} and Jiang, {Yan Yi} and Tyner, {Jeffrey W.} and Jianhong Ching and Kovalik, {Jean Paul} and Vikas Madan and Chan, {Shing Leng} and Markus M{\"u}schen and Breunig, {Joshua J.} and Lin, {De Chen} and Koeffler, {H. Phillip} and Cavenee, {Webster K.}",
note = "Funding Information: We thank Sumiko Takao and Vaidehi Krishnan for help with γ-radiation experiments; Annouck Luyten, Yi-Ting Qiao, and Kol-Jia Yong for ChIP protocols and technical support; Hui-Min Geng, Christian Hurtz, Anand Jeyasekharan, and Shojiro Kitajima for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse breeding. This work is funded by the National Research Foundation Singapore under its Singapore Translational Research Investigator Award (to H.P.K.; NMRC/STaR/0021/2014), the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150), the Singapore Ministry of Health's National Medical Research Council Centre Grant awarded to National University Cancer Institute of Singapore, the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiatives, and is additionally supported by philanthropic donations from the Melamed family and Blanche and Steven Koegler, as well as Tom Collier {"}Regatta for Hope{"} Foundation. We also acknowledge support from the Donna and Jesse Garber Awards for Cancer Research (D.-C.L), the Samuel Oschin Comprehensive Cancer Institute Cancer Research Forum Award (J.J.B.), the Board of Governors RMI of Cedars-Sinai (J.J.B.), and National Institutes of Health Grant R33 CA202900 (to J.J.B.).",
year = "2017",
doi = "10.1073/pnas.1609758114",
language = "English (US)",
volume = "114",
pages = "3981--3986",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "15",
}