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BRD4 inhibition suppresses histone H4 UFMylation to drive ferroptosis sensitivity through TXNIP

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298083 | GEO | 2025/11/25

REPOSITORIES: GEO

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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-Î± inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-Î±-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-Î± (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-Î± vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.

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BRD4 inhibition suppresses histone H4 UFMylation to drive ferroptosis sensitivity through TXNIP

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