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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...

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Autores principales: Zeng, Furong, Li, Yayun, Meng, Yu, Sun, Huiyan, He, Yi, Yin, Mingzhu, Chen, Xiang, Deng, Guangtong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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.
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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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