BRD4 inhibition suppresses histone H4 UFMylation to increase ferroptosis sensitivity through TXNIP.

ABSTRACT: Bromodomain Containing 4 (BRD4) inhibition selectively alters gene transcription, which subsequently influences cellular responses to BET inhibitors. The specific genes that mediate the effects of BET inhibitors in solid tumors remain inadequately characterized. In this study, we demonstrate that the BET inhibitor JQ1 induces the upregulation of Thioredoxin Interacting Protein (TXNIP), which mediates the anti-tumor effects of JQ1. Mechanistically, JQ1 reduces histone H3 Lysine 9 trimethylation within TXNIP promoter, enhancing its transcription in the presence of glucose. Increased TXNIP inhibits histone H4 UFMylation by disrupting the interaction between H4 and UFM1 binding protein 1 (UFBP1), a pivotal component mediating protein UFMylation. Rather than modulating cMYC expression directly,

SUBMITTER: Yang Z 

PROVIDER: S-EPMC12623952 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature