Concurrent targeting of MAP3K3 and BRD4 by miR-3140-3p overcomes acquired resistance to BET inhibitors in neuroblastoma cells

Chang Liu; Yasuyuki Gen; Kousuke Tanimoto; Tomoki Muramatsu; Jun Inoue; Johji Inazawa

Molecular Therapy: Nucleic Acids (Sep 2021)

Concurrent targeting of MAP3K3 and BRD4 by miR-3140-3p overcomes acquired resistance to BET inhibitors in neuroblastoma cells

Chang Liu,
Yasuyuki Gen,
Kousuke Tanimoto,
Tomoki Muramatsu,
Jun Inoue,
Johji Inazawa

Affiliations

Chang Liu: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Yasuyuki Gen: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Corresponding author: Yasuyuki Gen, Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kousuke Tanimoto: Genome Laboratory, Medical Research Institute, TMDU, Tokyo, Japan
Tomoki Muramatsu: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Jun Inoue: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Johji Inazawa: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Bioresource Research Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan; Corresponding author: Johji Inazawa, Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Journal volume & issue: Vol. 25
pp. 83 – 92

Abstract

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Neuroblastoma (NB) harboring MYCN amplification is a refractory disease with a poor prognosis. As BRD4, an epigenetic reader belonging to the bromodomain and extra terminal domain (BET) family, drives transcription of MYCN in NB cells, BET inhibitors (BETis) are considered useful for NB therapy. However, clinical trials of BETis suggested that early acquired resistance to BETis limits their therapeutic benefit. MicroRNAs are small non-coding RNAs that mediate post-transcriptional silencing of target genes. We previously identified miR-3140-3p as a potent candidate for nucleic acid therapeutics for cancer, which directly targets BRD4. We demonstrated that miR-3140-3p suppresses tumor cell growth in MYCN-amplified NB by downregulating MYCN and MYC through BRD4 suppression. We established BETi-acquired resistant NB cells to evaluate the mechanism of resistance to BETi in NB cells. We revealed that activated ERK1/2 stabilizes MYCN protein by preventing ubiquitin-mediated proteolysis via phosphorylation of MYCN at Ser62 in BETi-acquired resistant NB cells, thereby attenuating the effects of BETi in these cells. miR-3140-3p efficiently downregulated MYCN expression by directly targeting the MAP3K3-ERK1/2 pathway in addition to BRD4 suppression, inhibiting tumor cell growth in BETi-acquired resistant NB cells. This study suggests that miR-3140-3p has the potential to overcome resistance to BETi in NB.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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