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TitleThe oncogene BCL6 is up-regulated in glioblastoma in response to DNA damage, and drives survival after therapy.
Publication TypeJournal Article
Year of Publication2020
AuthorsFabre, Marie-Sophie, Stanton Nicole M., Slatter Tania L., Lee Samuel, Senanayake Dinindu, Gordon Rosemary M. A., M Castro Leticia, Rowe Matthew R., Taha Ahmad, Royds Janice A., Hung Noelyn, Melnick Ari M., and McConnell Melanie J.
JournalPLoS One
Volume15
Issue4
Paginatione0231470
Date Published2020
ISSN1932-6203
KeywordsAnimals, Brain Neoplasms, Cell Line, Tumor, DNA Damage, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Male, Mice, Mice, Inbred C57BL, Oncogenes, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcriptional Activation, Up-Regulation, Xenograft Model Antitumor Assays
Abstract

<p>The prognosis for people with the high-grade brain tumor glioblastoma is very poor, due largely to low cell death in response to genotoxic therapy. The transcription factor BCL6, a protein that normally suppresses the DNA damage response during immune cell maturation, and a known driver of B-cell lymphoma, was shown to mediate the survival of glioblastoma cells. Expression was observed in glioblastoma tumor specimens and cell lines. When BCL6 expression or activity was reduced in these lines, increased apoptosis and a profound loss of proliferation was observed, consistent with gene expression signatures suggestive of anti-apoptotic and pro-survival signaling role for BCL6 in glioblastoma. Further, treatment with the standard therapies for glioblastoma-ionizing radiation and temozolomide-both induced BCL6 expression in vitro, and an in vivo orthotopic animal model of glioblastoma. Importantly, inhibition of BCL6 in combination with genotoxic therapies enhanced the therapeutic effect. Together these data demonstrate that BCL6 is an active transcription factor in glioblastoma, that it drives survival of cells, and that it increased with DNA damage, which increased the survival rate of therapy-treated cells. This makes BCL6 an excellent therapeutic target in glioblastoma-by increasing sensitivity to standard DNA damaging therapy, BCL6 inhibitors have real potential to improve the outcome for people with this disease.</p>

DOI10.1371/journal.pone.0231470
Alternate JournalPLoS One
PubMed ID32320427
PubMed Central IDPMC7176076
Grant ListR35 CA220499 / CA / NCI NIH HHS / United States