Journal
CELL DEATH & DISEASE
Volume 10, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-019-1793-9
Keywords
-
Categories
Funding
- National Science & Technology Major Project of China [2018ZX09711002-011-018]
- Nova Development Program of the Shanghai Institute of Materia Medica
- Science and Technology Commission of Shanghai Municipality [19ZR1467900]
- National Natural Science Foundation of China [81330076]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020104]
- State Key Laboratory of Drug Research
- Open Studio for Drugability Research of Marine Natural Products in the Pilot National Laboratory for Marine Science and Technology (Qingdao, China)
Ask authors/readers for more resources
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-gamma). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-gamma-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-gamma 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available