BET Family Proteins Directly Regulate Constitutive TDO2 Transcription in Cancer Cells.

Kynurenine (Kyn), a tryptophan catabolite, is a key mediator of tumor-associated immunosuppression, and its production depends mainly on indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). IDO1 is potently induced by interferon-γ (IFN-γ), and its transcriptional regulation is well characterized. In contrast, TDO2 is clinically relevant in cancer, but the mechanism controlling its expression is unclear. Here, we show that bromodomain and extra-terminal domain (BET) proteins directly regulate TDO2 transcription in cancer cells. In multiple TDO2-expressing cell lines, BET inhibitor JQ1 and BET degrader dBET6 suppressed TDO2 transcription and protein expression, with dBET6 showing broader and more potent activity. Chromatin immunoprecipitation followed by quantitative PCR showed BET protein occupancy at the TDO2 promoter, consistent with direct promoter binding. This BET-dependent regulation was observed across diverse cancer cell contexts, indicating that TDO2 is a conserved and pharmacologically tractable BET target. When IDO1 expression was induced by IFN-γ, dBET6 suppressed IDO1 and TDO2 expression and reduced Kyn production. Taken together, these findings reveal a BET-dependent mechanism controlling TDO2 expression and provide a rationale for evaluating BET inhibition or degradation as a strategy to suppress Kyn production in cancer.