Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Nat Commun. 2021 Jun 28;12(1):4006. doi: 10.1038/s41467-021-24196-4.
MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
MYCN 激活是晚期神经母细胞瘤（NB）的标志，也是代谢重编程的已知主调控因子，有利于 NB 适应其微环境。我们发现，分子钟环的主要调节因子的表达在 MYCN 扩增的 NB 患者中受到严重破坏，这种破坏独立预测不良的临床结局。MYCN 通过直接结合其启动子，诱导时钟抑制剂的表达并下调时钟激活剂的表达。最终，通过抑制 BMAL1 的表达和振荡，MYCN 减弱了分子钟，从而促进细胞存活。通过其基因过表达和激动剂 SR1078 的刺激来重新建立时钟激活剂 RORα 的活性，恢复 BMAL1 的表达和振荡，有效地阻断 MYCN 介导的肿瘤生长和从头脂肪生成，并使 NB 肿瘤对常规化疗敏感。总之，通过阻断 MYCN 介导的分子钟和细胞代谢的失调，重新激活 RORα 可以作为治疗 MYCN 扩增型 NB 的一种治疗策略。
