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Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance.
Fang Tai, Kunxiang Gong, Kai Song, Yanling He, Jian Shi
Nature communications 2020 Jan 14
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BET bromodomain inhibitors (BETi), such as JQ1, have been demonstrated to effectively kill multiple types of cancer cells. However, the underlying mechanisms for BETi resistance remain largely unknown. Our evidences show that JQ1 treatment evicts BRD4 from the FOXD3-localized MIR548D1 gene promoter, leading to repression of miR-548d-3p. The loss of miRNA restores JunD expression and subsequent JunD-dependent transcription of RPS6KA2 gene. ERK1/2/5 kinases phosphorylate RSK3 (RPS6KA2), resulting in the enrichment of activated RSK3 and blockade of JQ1 killing effect. Dual inhibition of MEKs/ERKs or single EGFR inhibition are able to mimic the effect of JunD/RSK3-knockdown to reverse BETi resistance. Collectively, our study indicates that loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance, which can be reversed by targeting EGFR-MEK1/2/5-ERK1/2/5 signalling.
Citation
Fang Tai, Kunxiang Gong, Kai Song, Yanling He, Jian Shi.
Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance.
Nature communications.
2020 Jan 14;11(1):258
Mesh Tags
Antineoplastic Agents
Azepines
Cell Cycle Proteins
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
MicroRNAs
Mitogen-Activated Protein Kinase Kinases
Phosphorylation
Promoter Regions, Genetic
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-jun
Ribosomal Protein S6 Kinases, 90-kDa
Signal Transduction
Transcription Factors
Triazoles
Substances
(+)-JQ1 compound
Antineoplastic Agents
Azepines
BRD4 protein, human
Cell Cycle Proteins
FOXD3 protein, human
Forkhead Transcription Factors
JunD protein, human
MIRN548 microRNA, human
MicroRNAs
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-jun
Transcription Factors
Triazoles
ErbB Receptors
Ribosomal Protein S6 Kinases, 90-kDa
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase Kinases
PMID: 31937753
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