Concurrent targeting of MAP3K3 and BRD4 by miR-3140-3p overcomes acquired resistance to BET inhibitors in neuroblastoma cells.
Concurrent targeting of MAP3K3 and BRD4 by miR-3140-3p overcomes acquired resistance to BET inhibitors in neuroblastoma cells.
复制标题
miR-3140-3p同时靶向MAP3K3和BRD4克服了神经母细胞瘤细胞对BET抑制剂的获得性耐药。
DOI：
10.1016/j.omtn.2021.05.001
复制
发表时间：
2021-09-03
期刊：
影响因子：
--
通讯作者：
Inazawa J
中科院分区：
文献类型：
--
作者：
Liu C;Gen Y;Tanimoto K;Muramatsu T;Inoue J;Inazawa J
携带MYCN扩增的神经母细胞瘤是一种难治性疾病，预后不良。由于BRD 4（属于布罗莫结构域和额外末端结构域（BET）家族的表观遗传读取器）驱动NB细胞中MYCN的转录，BET抑制剂（BET）被认为可用于NB治疗。然而，BETis的临床试验表明，对BETis的早期获得性耐药性限制了其治疗益处。MicroRNA是介导靶基因转录后沉默的小的非编码RNA。我们之前鉴定了miR-3140- 3 p作为癌症核酸治疗剂的有效候选物，其直接靶向BRD 4。我们证明了miR-3140- 3 p通过BRD 4抑制下调MYCN和MYC来抑制MYCN扩增的NB中的肿瘤细胞生长。我们建立了BETi获得性耐药NB细胞，以评估NB细胞中对BETi的耐药机制。我们发现，活化的ERK 1/2通过阻止泛素介导的蛋白水解而稳定MYCN蛋白，所述蛋白水解经由在BETi获得性抗性NB细胞中MYCN在Ser 62处的磷酸化，从而减弱BETi在这些细胞中的作用。miR-3140- 3 p通过直接靶向MAP 3 K3-ERK 1/2途径以及BRD 4抑制有效下调MYCN表达，抑制BETi获得性耐药NB细胞中的肿瘤细胞生长。这项研究表明，miR-3140- 3 p有可能克服NB对BETi的耐药性。Liu及其同事发现，对BET抑制剂的获得性耐药性是通过神经母细胞瘤细胞中激活的ERK 1/2引起的MYCN蛋白的稳定化。miR-3140- 3 p通过抑制BRD 4转录下调MYCN表达，并通过MAP 3 K3-ERK 1/2途径转录后下调MYCN表达，从而克服了神经母细胞瘤细胞对BET抑制剂的获得性耐药性。
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. Liu and colleagues identified that acquired resistance to BET inhibitor was through the stabilization of MYCN protein due to activated ERK1/2 in neuroblastoma cells. miR-3140-3p downregulated MYCN expression transcriptionally by suppressing BRD4 and post-transcriptionally through the MAP3K3-ERK1/2 pathway, thereby overcoming the acquired resistance to BET inhibitor in neuroblastoma cells.
登录
查看更多内容
影响因子：
4.8
作者：
Bonvin, C;Guillon, A;Widmann, C
通讯作者：
Widmann, C
影响因子：
45.3
作者：
Lewin, Jeremy;Soria, Jean-Charles;Massard, Christophe
通讯作者：
Massard, Christophe
DOI：
10.1158/1541-7786.mcr-15-0477
发表时间：
2016-08
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Keller J;Nimnual AS;Varghese MS;VanHeyst KA;Hayman MJ;Chan EL
通讯作者：
Chan EL
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
--
作者：
Gen, Yasuyuki;Yasui, Kohichiroh;Yoshikawa, Toshikazu
通讯作者：
Yoshikawa, Toshikazu