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The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress

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. M...

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Autores principales: Liu, Yanan, Feng, Juanjuan, Yuan, Kun, Wu, Zhengzhen, Hu, Longmiao, Lu, Yue, Li, Kun, Guo, Jiawei, Chen, Jing, Ma, Chengbin, Pang, Xiufeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9064299/
https://www.ncbi.nlm.nih.gov/pubmed/35503721
http://dx.doi.org/10.7554/eLife.69255
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author Liu, Yanan
Feng, Juanjuan
Yuan, Kun
Wu, Zhengzhen
Hu, Longmiao
Lu, Yue
Li, Kun
Guo, Jiawei
Chen, Jing
Ma, Chengbin
Pang, Xiufeng
author_facet Liu, Yanan
Feng, Juanjuan
Yuan, Kun
Wu, Zhengzhen
Hu, Longmiao
Lu, Yue
Li, Kun
Guo, Jiawei
Chen, Jing
Ma, Chengbin
Pang, Xiufeng
author_sort Liu, Yanan
collection PubMed
description 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.
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spelling pubmed-90642992022-05-04 The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress Liu, Yanan Feng, Juanjuan Yuan, Kun Wu, Zhengzhen Hu, Longmiao Lu, Yue Li, Kun Guo, Jiawei Chen, Jing Ma, Chengbin Pang, Xiufeng eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2022-05-03 /pmc/articles/PMC9064299/ /pubmed/35503721 http://dx.doi.org/10.7554/eLife.69255 Text en © 2022, Liu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Liu, Yanan
Feng, Juanjuan
Yuan, Kun
Wu, Zhengzhen
Hu, Longmiao
Lu, Yue
Li, Kun
Guo, Jiawei
Chen, Jing
Ma, Chengbin
Pang, Xiufeng
The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title_full The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title_fullStr The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title_full_unstemmed The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title_short The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress
title_sort oncoprotein bcl6 enables solid tumor cells to evade genotoxic stress
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9064299/
https://www.ncbi.nlm.nih.gov/pubmed/35503721
http://dx.doi.org/10.7554/eLife.69255
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