Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31937753.
- Also identified by DOI 10.1038/s41467-019-14083-4 and PMC identifier 6959298.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Cell Cycle Proteins
- Drug Resistance, Neoplasm
- Forkhead Transcription Factors
- MicroRNAs
- Proto-Oncogene Proteins c-jun
- Ribosomal Protein S6 Kinases, 90-kDa
- Transcription Factors