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Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l-kynurenine. Here,...

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Autores principales: Tian, Chang-Qing, Chen, Lin, Chen, Hua-Dong, Huan, Xia-Juan, Hu, Jian-Ping, Shen, Jing-Kang, Xiong, Bing, Wang, Ying-Qing, Miao, Ze-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642217/
https://www.ncbi.nlm.nih.gov/pubmed/31324754
http://dx.doi.org/10.1038/s41419-019-1793-9
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author Tian, Chang-Qing
Chen, Lin
Chen, Hua-Dong
Huan, Xia-Juan
Hu, Jian-Ping
Shen, Jing-Kang
Xiong, Bing
Wang, Ying-Qing
Miao, Ze-Hong
author_facet Tian, Chang-Qing
Chen, Lin
Chen, Hua-Dong
Huan, Xia-Juan
Hu, Jian-Ping
Shen, Jing-Kang
Xiong, Bing
Wang, Ying-Qing
Miao, Ze-Hong
author_sort Tian, Chang-Qing
collection PubMed
description The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.
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spelling pubmed-66422172019-07-22 Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine Tian, Chang-Qing Chen, Lin Chen, Hua-Dong Huan, Xia-Juan Hu, Jian-Ping Shen, Jing-Kang Xiong, Bing Wang, Ying-Qing Miao, Ze-Hong Cell Death Dis Article The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers. Nature Publishing Group UK 2019-07-19 /pmc/articles/PMC6642217/ /pubmed/31324754 http://dx.doi.org/10.1038/s41419-019-1793-9 Text en © The Author(s) 2019 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/.
spellingShingle Article
Tian, Chang-Qing
Chen, Lin
Chen, Hua-Dong
Huan, Xia-Juan
Hu, Jian-Ping
Shen, Jing-Kang
Xiong, Bing
Wang, Ying-Qing
Miao, Ze-Hong
Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title_full Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title_fullStr Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title_full_unstemmed Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title_short Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
title_sort inhibition of the bet family reduces its new target gene ido1 expression and the production of l-kynurenine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642217/
https://www.ncbi.nlm.nih.gov/pubmed/31324754
http://dx.doi.org/10.1038/s41419-019-1793-9
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