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

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.

Cell‐Based Identification of New IDO1 Modulator Chemotypes

“…of IDO1. [19] In line with this, BRD4 inhibitors, such as PFI-1, decreased Kyn levels in cells (Table 1). The second group was comprised of small molecules like succinylacetone that interfere with cellular heme synthesis, reduce the abundance of the cofactor and thereby impair IDO1 activity (Table 1).…”

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

“…However, the major signaling pathways inducing immunosenescence involve the TGF-β/SMAD and the IL-10/STAT3 pathways which are known to control the activity of several important epigenetic regulators, e.g., DNA methyltransferases and histone demethylases [164,167]. In addition, the expression of TGF-β1, IL-10, AhR, and IDO1 genes are the subject of complex epigenetic regulation [168][169][170][171]. Epigenetic mechanisms also regulate the activity of the immunosuppressive network, e.g., by controlling the expression of FoxP3 gene, the master gene of Tregs [172].…”

The BET family in immunity and disease

“…For example, investigators have found that BRD2, BRD3, and BRD4 directly bind to H3K27Ac at the promoter of 2, 3-dioxygenase 1 (IDO1) that mediates metabolism-related immune escape in cancer. 126 The combination of BRD4 and H3K27Ac also facilitates the formation of SEs, which drives the transcription of NF-κB target genes (MT-CO2 and TGFB2), and then promotes the production of the extracellular matrix, myofibroblast differentiation, and tumor-associated inflammation. 127 , 128 In addition, BETi (e.g., I-BET151) inhibits the deposition of H3K27Ac at the promoters of proinflammatory cytokines (TNF and IL6) induced by β-glucan.…”

“… 48 Apart from CD274, BETs also directly promote the expression of IDO1, an immune checkpoint that mediates metabolic immune escape in cancer through the production of L-kynurenine. 126 Collectively, the evasion of immune surveillance by BETs covers multiple immunosuppressive mechanisms. The combination of BETi and traditional chemotherapy may restore or enhance antitumor immunity.…”