Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
Cell Death Dis. 2020 May 14;11(5):368. doi: 10.1038/s41419-020-2563-4.
Despite the improvement in clinical outcome with 13-cis-retinoic acid (13-cisRA) + anti-GD2 antibody + cytokine immunotherapy given in first response ~40% of high-risk neuroblastoma patients die of recurrent disease. MYCN genomic amplification is a biomarker of aggressive tumors in the childhood cancer neuroblastoma. MYCN expression is downregulated by 13-cisRA, a differentiating agent that is a component of neuroblastoma therapy. Although MYC amplification is rare in neuroblastoma at diagnosis, we report transcriptional activation of MYC medicated by the transcription factor OCT4, functionally replacing MYCN in 13-cisRA-resistant progressive disease neuroblastoma in large panels of patient-derived cell lines and xenograft models. We identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by MAPKAPK2 (MK2). OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation. Expression of OCT4, MK2, and c-MYC was higher in progressive disease relative to pre-therapy neuroblastomas and was associated with inferior patient survival. OCT4 or MK2 knockdown decreased c-MYC expression and restored the sensitivity to 13-cisRA. In conclusion, we demonstrated that high c-MYC expression independent of genomic amplification is associated with disease progression in neuroblastoma. MK2-mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.
尽管在首次治疗中使用 13-顺式维甲酸（13-cisRA）+抗 GD2 抗体+细胞因子免疫疗法改善了临床结局，但仍有约 40%的高危神经母细胞瘤患者死于疾病复发。MYCN 基因扩增是儿童癌症神经母细胞瘤中侵袭性肿瘤的生物标志物。MYCN 表达受 13-cisRA 的下调调控，13-cisRA 是神经母细胞瘤治疗的一种分化剂。虽然 MYC 扩增在神经母细胞瘤诊断时很少见，但我们报告了转录因子 OCT4 介导的 MYC 转录激活，该激活在 13-cisRA 耐药进展性神经母细胞瘤中替代了 MYCN，在大量患者来源的细胞系和异种移植模型中得到了证实。我们在 MYC 启动子/增强子区域中鉴定了新的 OCT4 结合位点，该结合位点通过 MAPKAPK2（MK2）磷酸化调节 MYC 表达。MK2 在 S111 残基上对 OCT4 的磷酸化是 MYC 转录激活的上游事件。与治疗前神经母细胞瘤相比，进展性疾病中 OCT4、MK2 和 c-MYC 的表达更高，并且与患者生存不良相关。OCT4 或 MK2 的敲低降低了 c-MYC 的表达并恢复了对 13-cisRA 的敏感性。总之，我们证明了独立于基因组扩增的高 c-MYC 表达与神经母细胞瘤的疾病进展相关。MK2 介导的 OCT4 转录激活是进展性神经母细胞瘤中激活 MYC 癌基因的新机制，为治疗提供了一个靶点。
