Back to Search
Start Over
Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
- Source :
- Cell Death and Disease, Vol 10, Iss 8, Pp 1-13 (2019), Cell Death & Disease
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Gene Expression
Cancer immunotherapy
Cell Cycle Proteins
RNA polymerase II
Histones
Mice
0302 clinical medicine
Gene expression
Promoter Regions, Genetic
Kynurenine
Mice, Inbred BALB C
Sulfonamides
biology
Chemistry
lcsh:Cytology
Acetylation
hemic and immune systems
Tumor Burden
030220 oncology & carcinogenesis
Female
BRD4
Pyridones
Immunology
Mice, Nude
HL-60 Cells
chemical and pharmacologic phenomena
Transfection
Article
BET inhibitor
03 medical and health sciences
Cellular and Molecular Neuroscience
Histone H3
Animals
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
RNA, Messenger
lcsh:QH573-671
Messenger RNA
RNA
Cell Biology
Xenograft Model Antitumor Assays
Molecular biology
Bromodomain
030104 developmental biology
A549 Cells
biology.protein
Immunosuppression
HeLa Cells
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 10
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....9a8e1400201c579037c4840db413849f