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

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, H4 UFMylation facilitates the chromatin binding of cMYC to promote the transcription of cell cycle regulatory genes. Furthermore, TXNIP inhibits the proteasomal degradation of P27, a cyclin-dependent kinase (CDK) inhibitor. Consequently, solid cancer cells treated with JQ1 enter a dormant state which is associated with cancer relapse and drug tolerance. Nevertheless, these quiescent cells exhibit sensitivity to ferroptosis, suggesting that BET inhibitors enhance the anti-tumor efficacy of ferroptosis inducers. Collectively, our findings elucidate the regulators of protein UFMylation and cMYC activity, which modulate cellular responses to BET inhibitors and ferroptosis inducers in solid cancer cells.