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The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression.


ABSTRACT: 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?/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.

SUBMITTER: Xiong Y 

PROVIDER: S-EPMC6748082 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression.

Xiong Yu Y   Li Linli L   Zhang Liting L   Cui Yangyang Y   Wu Chengyong C   Li Hui H   Chen Kai K   Yang Qiuyuan Q   Xiang Rong R   Hu Yiguo Y   Huang Shile S   Wei Yuquan Y   Yang Shengyong S  

Cell death and differentiation 20190115 10


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 TNFα/Smac-mimetic/Z-VAD-FMK (TSZ)-induced cell  ...[more]

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