BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress

Abstract

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 HSF1driven 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 fi nd 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 TOX , 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.

BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors

“…However, the biological role of BCL6 in solid tumors has been hard to determine, given its low basal content. Our findings (Figure 1), along with recently published studies (21,47), support an underestimated function of BCL6 in stressed conditions, in which BCL6 expression can be induced as a consequence of either an increase in its gene transcription or a decrease in its protein degradation. Increased BCL6 expression promotes carcinogenesis and drug resistance by transrepressing a variety of tumor suppressor genes, such as TP53 (13, 49), CDKN1A (50), PTEN (51), DUSP5 (19), and CASP8 (19).…”

“…Apart from inhibition of the BTB domain, compounds that induced rapid BCL6 protein degradation or targeted a tyrosine residue in the homodimer interface (58) also demonstrated antitumor efficacy. Although BCL6 inhibition has proven to be effective as a monotherapy, our findings, together with those of other studies (21,47), characterize a critical role of BCL6 in mediating stress tolerance. Therefore, it is of great importance to further evaluate the benefit of BCL6 inhibitors as combinative regimens to conquer BCL6-mediated drug resistance.…”

“…Compounds selectively targeting BCL6 activity have demonstrated promising antitumor effects in preclinical settings (19,20). Recent work has shown that BCL6 serves as a central component of the stress response and tumorigenesis, in which inhibition of BCL6 might potentiate chemotherapeutic sensitivity (21,22). These findings highlighted a key role of BCL6 in conferring cancer cell resistance to therapeutic agents.…”

The oncogene BCL6 is up-regulated in glioblastoma in response to DNA damage, and drives survival after therapy

“…Even in the cell lines that had low basal levels of endogenous BCL6, DNA damaging therapy induced substantial increases in BCL6. This appears to be a conserved response to stress [37] acquired by glioblastoma that drives extensive resistance to therapy.…”

Compartments and Connections Within the Germinal Center

“…The GC B cell molecular program establishes a state that promotes survival in the presence of increased genomic stress ( 7 , 8 ). This both enables SHM and increases the risk of lymphoma ( 9 , 10 ). Indeed, GC B cells are precursors for large B cell lymphoma, follicular lymphoma, and Burkitt lymphoma ( 11 , 12 ).…”