TitleBCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress.
Publication TypeJournal Article
Year of Publication2019
AuthorsFernando, Tharu M., Marullo Rossella, Gresely Benet Pera, Phillip Jude M., Yang Shao Ning, Lundell-Smith Geoffrey, Torregroza Ingrid, Ahn Haelee, Evans Todd, Gyorffy Balazs, Prive Gilbert G., Hirano Masayuki, Melnick Ari M., and Cerchietti Leandro
JournalCancer Discov
Volume9
Issue5
Pagination662-679
Date Published2019 05
ISSN2159-8290
KeywordsAdaptation, Physiological, Animals, Apoptosis, B-Lymphocytes, Cell Proliferation, Cells, Cultured, Female, Germinal Center, Heat Shock Transcription Factors, Heat-Shock Response, Heterografts, Humans, Male, Mice, Mice, Knockout, Mice, SCID, Neoplasms, Proto-Oncogene Proteins c-bcl-6, Stress, Physiological
Abstract

<p>Several lines of evidence link the canonical oncogene BCL6 to stress response. Here we demonstrate that BCL6 evolved in vertebrates as a component of the HSF1-driven stress response, which has been co-opted by the immune system to support germinal center formation and may have been decisive in the convergent evolution of humoral immunity in jawless and jawed vertebrates. We find that the highly conserved BTB corepressor binding site of BCL6 mediates stress adaptation across vertebrates. We demonstrate that pan-cancer cells hijack this stress tolerance mechanism to aberrantly express BCL6. Targeting the BCL6 BTB domain in cancer cells induces apoptosis and increases susceptibility to repeated doses of cytotoxic therapy. The chemosensitization effect upon BCL6 BTB inhibition is dependent on the derepression of , implicating modulation of DNA repair as a downstream mechanism. Collectively, these data suggest a form of adaptive nononcogene addiction rooted in the natural selection of BCL6 during vertebrate evolution. SIGNIFICANCE: We demonstrate that HSF1 drives BCL6 expression to enable stress tolerance in vertebrates. We identify an HSF1-BCL6-TOX stress axis that is required by cancer cells to tolerate exposure to cytotoxic agents and points toward BCL6-targeted therapy as a way to more effectively kill a wide variety of solid tumors..</p>

DOI10.1158/2159-8290.CD-17-1444
Alternate JournalCancer Discov
PubMed ID30777872
PubMed Central IDPMC6497559
Grant ListP50 CA192937 / CA / NCI NIH HHS / United States
R01 HL111400 / HL / NHLBI NIH HHS / United States
R01 GM100151 / GM / NIGMS NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
F31 CA167999 / CA / NCI NIH HHS / United States
R01 AI072435 / AI / NIAID NIH HHS / United States
/ / CIHR / Canada