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BRD4 inhibition suppresses histone H4 UFMylation to increase ferroptosis sensitivity through TXNIP
Zhen Yang1, Baoshuai Wang1, Bin Guo1
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
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, 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.
Insights
BET inhibitor JQ1 upregulates TXNIP, mediating anti-tumor effects by inhibiting histone modification and promoting cell dormancy. Dormant cells are sensitive to ferroptosis, enhancing combination therapy potential.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Bromodomain and Extra-Terminal (BET) inhibitors, like JQ1, alter gene transcription but their specific targets in solid tumors are unclear.
- Understanding these targets is crucial for optimizing BET inhibitor efficacy in cancer treatment.
Purpose of the Study:
- To identify genes mediating the anti-tumor effects of BET inhibitor JQ1 in solid tumors.
- To elucidate the molecular mechanisms by which JQ1 impacts gene transcription, protein modification, and cell fate.
- To explore the implications of these findings for combination therapies.
Main Methods:
- Treatment of solid cancer cells with BET inhibitor JQ1.
- Analysis of gene transcription, histone modifications (H3K9 trimethylation, H4 UFMylation), and protein stability (P27).
- Investigation of the roles of Thioredoxin Interacting Protein (TXNIP) and UFMylation in cellular response to JQ1.
Main Results:
- JQ1 upregulates TXNIP, which mediates its anti-tumor effects by reducing H4 UFMylation and inhibiting cMYC-driven cell cycle progression.
- Increased TXNIP inhibits H4 UFMylation by disrupting UFBP1 interaction, impacting cMYC chromatin binding.
- JQ1 treatment induces a dormant state in cancer cells, increasing P27 stability and conferring sensitivity to ferroptosis.
Conclusions:
- TXNIP is a key mediator of JQ1's anti-tumor activity, influencing epigenetic regulation and cell cycle control.
- BET inhibition induces cancer cell dormancy, which can be overcome by ferroptosis inducers, suggesting novel therapeutic strategies.
- These findings provide insights into the regulation of protein UFMylation and cMYC activity in response to BET inhibitors.
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