1. Academic Validation
  2. The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress

The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress

  • Elife. 2022 May 3;11:e69255. doi: 10.7554/eLife.69255.
Yanan Liu  # 1 Juanjuan Feng  # 1 Kun Yuan 1 Zhengzhen Wu 1 Longmiao Hu 1 Yue Lu 1 Kun Li 1 Jiawei Guo 2 Jing Chen 3 Chengbin Ma 1 Xiufeng Pang 1
Affiliations

Affiliations

  • 1 Changning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
  • 2 Department of Thoracic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
  • 3 Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, China.
  • # Contributed equally.
Abstract

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 solid 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 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 solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.

Keywords

BCL6; adaptive resistance; cancer biology; combination chemotherapy; genotoxic agents; immunology; inflammation; interferon responses; mouse.

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