PT  - JOURNAL ARTICLE
AU  - Yanan Liu
AU  - Juanjuan Feng
AU  - Kun Yuan
AU  - Yue Lu
AU  - Kun Li
AU  - Jiawei Guo
AU  - Chengbin Ma
AU  - Jing Chen
AU  - Xiufeng Pang
TI  - The Oncoprotein BCL6 Enables Cancer Cells to Evade Genotoxic Stress
AID  - 10.1101/2021.06.15.448559
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.15.448559
4099  - http://biorxiv.org/content/early/2021/06/15/2021.06.15.448559.short
4100  - http://biorxiv.org/content/early/2021/06/15/2021.06.15.448559.full
AB  - Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were selectively and substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.Competing Interest StatementThe authors have declared no competing interest.