Journal
CELL DEATH AND DIFFERENTIATION
Volume 26, Issue 10, Pages 1929-1941Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-018-0262-9
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Funding
- National Natural Science Foundation of China [81473140, 81573349, 81773633, 21772130]
- National Science and Technology Major Project [2018ZX09711002-014-002, 2018ZX09711002-011-019, 2018ZX09711003-003-006]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
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Necroptosis is a programmed form of necrotic cell death, which is tightly regulated by the necroptotic signaling pathway containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL) protein. In addition to the RIP1-RIP3-MLKL axis, other factors regulating necroptosis are still largely unknown. Here a cell-based small-molecule screening led to the finding that BET inhibitors protected cells from necroptosis in the TNF alpha/Smac-mimetic/Z-VAD-FMK (TSZ)-induced cell necroptosis model. Mechanistic studies revealed that BET inhibitors acted by downregulating MLKL expression. Further research demonstrated that BRD4, IRF1, P-TEFb, and RNA polymerase II formed a transcription complex to regulate the expression of MLKL, and BET inhibitors interfered with the transcription complex formation. In necroptosis-related disease model, the BET inhibitor JQ-1 showed promising therapeutic effects. Collectively, our studies establish, for the first time, BRD4 as a new epigenetic factor regulating necroptosis, and highlight the potential of BET inhibitors in the treatment of necroptosis-related diseases.
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