Journal Article

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

Gong, Kunxiang, Tai, Fang, Song, Kai, He, Yanling, Shi, Jian

2020

Overview

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. The clinical use of BET inhibitors (BETi) is limited by primary and acquired resistance. Here, the authors report that BETi resistance is determined by JunD/RSK3 signalling activation induced by the loss of BRD4/Foxd3/miR-548d-3p, which can be reverted by targeting the EGFR-MEK-ERK pathway.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/109 / 13/2 / 13/31 / 13/89 / 13/95 / 38 / 38/15 / 38/77 / 631/67 / 631/67/1059/2326 / 631/80 / 692/4028/67/1347 / Antineoplastic Agents - pharmacology / Azepines - pharmacology / Cell Cycle Proteins - antagonists & inhibitors / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Line, Tumor / Drug Resistance, Neoplasm / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - metabolism / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors / Extracellular Signal-Regulated MAP Kinases - metabolism / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockdown Techniques / Humanities and Social Sciences / Humans / Inhibitors / Kinases / Metabolic pathways / MicroRNAs - genetics / miRNA / Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors / Mitogen-Activated Protein Kinase Kinases - metabolism / multidisciplinary / Phosphorylation / Promoter Regions, Genetic / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-jun - genetics / Proto-Oncogene Proteins c-jun - metabolism / Ribosomal Protein S6 Kinases, 90-kDa - genetics / Ribosomal Protein S6 Kinases, 90-kDa - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Signaling / Transcription / Transcription Factors - antagonists & inhibitors / Transcription Factors - genetics / Transcription Factors - metabolism / Triazoles - pharmacology