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BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression
Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to comb...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981764/ https://www.ncbi.nlm.nih.gov/pubmed/36720918 http://dx.doi.org/10.1038/s12276-023-00936-y |
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author | Zeng, Furong Li, Yayun Meng, Yu Sun, Huiyan He, Yi Yin, Mingzhu Chen, Xiang Deng, Guangtong |
author_facet | Zeng, Furong Li, Yayun Meng, Yu Sun, Huiyan He, Yi Yin, Mingzhu Chen, Xiang Deng, Guangtong |
author_sort | Zeng, Furong |
collection | PubMed |
description | Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to combine JQ1 with 240 antitumor drugs from the Food and Drug Administration (FDA)-approved drug library and found that sunitinib synergizes with BET inhibitors in melanoma cells. We further demonstrated that BET inhibitors synergize with sunitinib in melanoma by inducing apoptosis and cell cycle arrest. Mechanistically, BET inhibitors sensitize melanoma cells to sunitinib by inhibiting GDF15 expression. Strikingly, GDF15 is transcriptionally regulated directly by BRD4 or indirectly by the BRD4/IL6/STAT3 axis. Xenograft assays revealed that the combination of BET inhibitors with sunitinib causes melanoma suppression in vivo. Altogether, these findings suggest that BET inhibitor-mediated GDF15 inhibition plays a critical role in enhancing sunitinib sensitivity in melanoma, indicating that BET inhibitors synergize with sunitinib in melanoma. |
format | Online Article Text |
id | pubmed-9981764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99817642023-03-04 BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression Zeng, Furong Li, Yayun Meng, Yu Sun, Huiyan He, Yi Yin, Mingzhu Chen, Xiang Deng, Guangtong Exp Mol Med Article Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to combine JQ1 with 240 antitumor drugs from the Food and Drug Administration (FDA)-approved drug library and found that sunitinib synergizes with BET inhibitors in melanoma cells. We further demonstrated that BET inhibitors synergize with sunitinib in melanoma by inducing apoptosis and cell cycle arrest. Mechanistically, BET inhibitors sensitize melanoma cells to sunitinib by inhibiting GDF15 expression. Strikingly, GDF15 is transcriptionally regulated directly by BRD4 or indirectly by the BRD4/IL6/STAT3 axis. Xenograft assays revealed that the combination of BET inhibitors with sunitinib causes melanoma suppression in vivo. Altogether, these findings suggest that BET inhibitor-mediated GDF15 inhibition plays a critical role in enhancing sunitinib sensitivity in melanoma, indicating that BET inhibitors synergize with sunitinib in melanoma. Nature Publishing Group UK 2023-02-01 /pmc/articles/PMC9981764/ /pubmed/36720918 http://dx.doi.org/10.1038/s12276-023-00936-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zeng, Furong Li, Yayun Meng, Yu Sun, Huiyan He, Yi Yin, Mingzhu Chen, Xiang Deng, Guangtong BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title | BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title_full | BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title_fullStr | BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title_full_unstemmed | BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title_short | BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression |
title_sort | bet inhibitors synergize with sunitinib in melanoma through gdf15 suppression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981764/ https://www.ncbi.nlm.nih.gov/pubmed/36720918 http://dx.doi.org/10.1038/s12276-023-00936-y |
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