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BCL6 Enables Cancer Cells to Evade Genotoxic Stress

ABSTRACT: Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, clinical benefit is often countered by a rapid adaptive response in tumors. Here we report that the proto-oncogene BCL6 is a core component conferring tumor resistance adaption. In response to genotoxic stress, BCL6 transcription was markedly promoted in cancer cells. BCL6 upregulation was positively associated with therapy resistance and poor progression-free survival in patients. Mechanistically, we discovered that treatment of the genotoxic agent etoposide led to transcriptional reprogramming of multiple proinflammatory cytokines, among which interferon-α and interferon-γ response were significantly enriched in resistant cells. Our results further revealed that the interferon/STAT1 axis that was required for the therapeutic efficacy of etoposide directly regulated BCL6 expression. Increased BCL6 consequently activated mTOR pathway through repressing the tumor suppressor PTEN to enable cancer cell survival. Importantly, targeted inhibition of BCL6 potentiated etoposide-triggered DNA damage and apoptosis in vitro and in vivo. Collectively, our findings highlight the significance of targeting previously uncharacterized interferon-mediated BCL6 pathway to conquer tolerance of cancer cells to genotoxic stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161803 | GEO | 2021/11/19

REPOSITORIES: GEO

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Project description:Radiation and chemotherapy represent standard-of-care cancer treatments, however most treated patients eventually experience tumor recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate molecular mechanisms of resistance to radio- and chemo-therapy, we exposed human cancer cell lines (HeLa, MCF-7, and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations including non-adherent fraction. Stress-mobilized non-adherent cell fractions differed from other survivors in deregulation of hundreds of genes including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in development of a heterogeneous non-adherent fraction comprising, besides apoptotic/necrotic cells, also live cells featuring active Notch signaling and expressing stem cell markers. Interferon-gamma-mediated loss of adhesion and anoikis-resistance required active Erk pathway interlinked with interferon signaling by IRF1, as chemical inhibition of MEK or siRNA-mediated knockdown of Erk1/2 and IRF1 prevented mobilization of the surviving non-adherent population. Noteworthy, among the top scoring genes upregulated in surviving non-adherent tumor cells induced by 5-azacytidine or irradiation was a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN resulted in suppression of the non-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively. Consistently, ectopic expression of SBSN isoforms enhanced the non-adherent phenotype, suggesting functional participation of SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. The stress-induced expression of skin protein(s) in a subset of cancer cells indicates partial induction of a keratinocyte-like expression program. Overall, we propose that IFN and Erk signaling drive the heterogeneous response of cancer cells to genotoxic therapies and expression of keratinocyte-specific genes as key players in mobilization and survival of cancer stem-like cells, with implications for cancer evolution and therapy resistance.

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BCL6 Enables Cancer Cells to Evade Genotoxic Stress

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