| First Author | Xiong Y | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 10 | Pages | 1929-1941 |
| PubMed ID | 30644439 | Mgi Jnum | J:305139 |
| Mgi Id | MGI:6510160 | Doi | 10.1038/s41418-018-0262-9 |
| Citation | Xiong Y, et al. (2019) The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression. Cell Death Differ 26(10):1929-1941 |
| abstractText | 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 TNFalpha/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. |
