Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance
Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance
复制标题
由于 BRD4/FOXD3/miR-548d-3p 轴缺失而增强的 JunD/RSK3 信号传导决定了 BET 抑制抗性
DOI：
10.1038/s41467-019-14083-4
复制
发表时间：
2020-01-14
影响因子：
16.6
通讯作者：
Shi, Jian
中科院分区：
文献类型：
--
作者：
Tai, Fang;Gong, Kunxiang;Shi, Jian
BET溴结构域抑制剂（BETi），如JQ1，已被证明能有效杀死多种类型的癌细胞。然而，BETi耐药的潜在机制在很大程度上仍然未知。我们的证据表明，JQ1处理使BRD4从FOXD3定位的MIR548D1基因启动子上脱离，导致miR - 548d - 3p的抑制。微小RNA的缺失恢复了JunD的表达以及随后RPS6KA2基因的JunD依赖性转录。ERK1/2/5激酶使RSK3（RPS6KA2）磷酸化，导致活化的RSK3富集并阻断JQ1的杀伤作用。MEKs/ERKs的双重抑制或单一的EGFR抑制能够模拟JunD/RSK3敲低的效果来逆转BETi耐药性。总之，我们的研究表明，BRD4/FOXD3/miR - 548d - 3p轴的缺失增强了JunD/RSK3信号传导并决定了BET抑制耐药性，而通过靶向EGFR - MEK1/2/5 - ERK1/2/5信号传导可以逆转这种耐药性。BET抑制剂（BETi）的临床应用受到原发性和获得性耐药的限制。在此，作者报告说，BETi耐药性是由BRD4/Foxd3/miR - 548d - 3p缺失诱导的JunD/RSK3信号激活所决定的，通过靶向EGFR - MEK - ERK途径可以逆转这种耐药性。
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.