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The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
Yanan Liu1, Juanjuan Feng1, Kun Yuan1
1Changning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
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.
Insights
The oncoprotein B cell lymphoma 6 (BCL6) drives solid tumor resistance to genotoxic cancer therapies. Inhibiting BCL6 enhances treatment efficacy by increasing DNA damage and apoptosis, suggesting combination therapy potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Genotoxic agents are crucial cancer treatments but face challenges from rapid tumor adaptive resistance.
- The role of specific oncoproteins in mediating this resistance is not fully understood.
Purpose of the Study:
- To investigate the role of B cell lymphoma 6 (BCL6) in conferring solid tumor adaptive resistance to genotoxic stress.
- To elucidate the molecular mechanisms by which BCL6 contributes to therapeutic resistance.
Main Methods:
- Analysis of BCL6 transactivation in response to various genotoxic agents.
- Investigating the link between BCL6, pro-inflammatory cytokines (interferon-α, interferon-γ), and the interferon/signal transducer and activator of transcription 1 (STAT1) axis.
- Assessing the impact of BCL6 inhibition on etoposide-induced DNA damage and apoptosis in vitro and in vivo.
Main Results:
- BCL6 transactivation correlated with reduced therapeutic efficacy and poorer clinical outcomes across multiple genotoxic agents.
- Genotoxic stress reprogrammed cytokine expression, enriching interferon-α and interferon-γ responses in resistant cells.
- The interferon/STAT1 axis directly upregulated BCL6, which repressed the tumor suppressor PTEN, promoting cancer cell survival.
- Targeted BCL6 inhibition significantly enhanced etoposide-induced DNA damage and apoptosis.
Conclusions:
- BCL6 is a key mediator of solid tumor adaptive resistance to genotoxic stress.
- Targeting BCL6 in combination with genotoxic agents offers a promising therapeutic strategy to overcome treatment resistance.
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