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Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance

Author

Listed:
  • Fang Tai

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Kunxiang Gong

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Kai Song

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Yanling He

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Jian Shi

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

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.

Suggested Citation

  • Fang Tai & Kunxiang Gong & Kai Song & Yanling He & Jian Shi, 2020. "Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14083-4
    DOI: 10.1038/s41467-019-14083-4
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