BRD4 inhibition suppresses histone H4 UFMylation to drive ferroptosis sensitivity through TXNIP
BRD4 inhibition selectively changes gene transcription which defines cell responses to BET inhibitors. Altered genes driving cell cycle arrest in solid tumor upon BET inhibitor treatment are far from clear. Here, we find that BET inhibitor JQ1 upregulates TXNIP which mediates the anti-tumor effects of JQ1. Mechanistically, JQ1 reduces histone H3K9 trimethylation at TXNIP promoter, facilitating its transcription in the presence of glucose. Increased TXNIP inhibits Histone H4 UFMylation by interfering the interaction between H4 and UFBP1. Instead of regulating cMYC expression, H4 UFMylation promotes the chromatin binding of cMYC to facilitate the transcription of cell-cycle related genes. Additionally, TXNIP prevents proteasomal degradation of P27, a CDK inhibitor. JQ1-treated solid cancer cells thus enter dormant state which is associated with cancer relapse and drug tolerance. However, these arrested cells are sensitive to ferroptosis, suggesting enhancing the functions of ferroptosis inducers with BET inhibitors. Together, our studies reveal regulators of protein UFMylation and cMYC activity, which modulate cell responses to BET inhibitors and ferroptosis inducers in solid cancer cells. Overall design: RNA-Seq profiling of DMSO and JQ1 treated HepG2 cells