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.
Highlights
The bromodomain and extra terminal domain (BET)family consists of BRD2, BRD3, BRD4, and BRDT
Its RNA profiling assayed by RNA sequencing (RNA-seq) showed that expression of 333 and 355 genes was downregulated in Ty-82 cells treated with this compound for 12 and 24 h, respectively (Fig. 1a, and Supplementary Tables S1 and S2)
Other well-known BET inhibitors, such as ABBV-075, JQ1, and OTX015, were used to continue the study to demonstrate the relationships between the BET family and IDO1
Summary
The bromodomain and extra terminal domain (BET)family consists of BRD2, BRD3, BRD4, and BRDT. Except for BRDT that is restricted to the testes, the other BET family members are extensively expressed in human tissues and act as acetylation readers to activate polymerase II (Pol II) by recruiting the transcription elongation factor b Cyclin. The BET family has been reported to regulate the expression of PD-L17,8 and several DNA repair factors[9], which can be inhibited by BET inhibitors. These findings offer a possibility that BET inhibitors are combined with anti-PD-L1 therapeutics or PARP inhibitors for cancer therapy, greatly expanding the potential therapeutic scope of BET inhibitors[7,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
