2. Academic Validation
  3. Inhibition of the BET family reduces its new target gene IDO1 expression and the production of L-kynurenine

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

  • Cell Death Dis. 2019 Jul 19;10(8):557. doi: 10.1038/s41419-019-1793-9.
Chang-Qing Tian 1 2,  Lin Chen 3,  Hua-Dong Chen 1 2,  Xia-Juan Huan 1,  Jian-Ping Hu 2 3,  Jing-Kang Shen 2 3,  Bing Xiong 4 5,  Ying-Qing Wang 6 7,  Ze-Hong Miao 8 9 10
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China.
  • 3 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
  • 4 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 5 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. [email protected].
  • 6 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. [email protected].
  • 7 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 8 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. [email protected].
  • 9 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 10 Open Studio for Drugability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 266237, Shandong, China. [email protected].
PMID: 31324754 DOI: 10.1038/s41419-019-1793-9
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.

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