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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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69255 |
| _version_ | 1811203583679397888 |
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| author | Yanan Liu Juanjuan Feng Kun Yuan Zhengzhen Wu Longmiao Hu Yue Lu Kun Li Jiawei Guo Jing Chen Chengbin Ma Xiufeng Pang |
| author_facet | Yanan Liu Juanjuan Feng Kun Yuan Zhengzhen Wu Longmiao Hu Yue Lu Kun Li Jiawei Guo Jing Chen Chengbin Ma Xiufeng Pang |
| author_sort | Yanan Liu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T02:57:46Z |
| format | Article |
| id | doaj.art-e7c169f84800472e81c9cfc2cf641fdd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:57:46Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e7c169f84800472e81c9cfc2cf641fdd2022-12-22T03:50:45ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.69255The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stressYanan Liu0Juanjuan Feng1Kun Yuan2Zhengzhen Wu3Longmiao Hu4Yue Lu5Kun Li6Jiawei Guo7Jing Chen8Chengbin Ma9Xiufeng Pang10https://orcid.org/0000-0002-4271-8710Changning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaDepartment of Thoracic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaKey Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaChangning Maternity and Infant Health Hospital, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaGenotoxic 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.https://elifesciences.org/articles/69255genotoxic agentsadaptive resistanceBCL6interferon responsescombination chemotherapy |
| spellingShingle | Yanan Liu Juanjuan Feng Kun Yuan Zhengzhen Wu Longmiao Hu Yue Lu Kun Li Jiawei Guo Jing Chen Chengbin Ma Xiufeng Pang The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress eLife genotoxic agents adaptive resistance BCL6 interferon responses combination chemotherapy |
| 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 | genotoxic agents adaptive resistance BCL6 interferon responses combination chemotherapy |
| url | https://elifesciences.org/articles/69255 |
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