Xiang Senfeng, Chen Pengfei, Shi Xiaoxian, Cai Hanqi, Shen Zihan, Liu Luyang, Xu Aixiao, Zhang Jianhua, Zhang Xingya, Bing Shaowei, Wang Jinhu, Shao Xuejing, Cao Ji, Yang Bo, He Qiaojun, Ying Meidan
Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Nanhu Brain-Computer Interface Institute, Hangzhou, China.
J Clin Invest. 2025 Jun 10;135(14). doi: 10.1172/JCI176655. eCollection 2025 Jul 15.
The N-Myc gene MYCN amplification accounts for the most common genetic aberration in neuroblastoma and strongly predicts the aggressive progression and poor clinical prognosis. However, clinically effective therapies that directly target N-Myc activity are limited. N-Myc is a transcription factor, and its stability is tightly controlled by ubiquitination-dependent proteasomal degradation. Here, we discovered that Kelch-like protein 37 (KLHL37) played a crucial role in enhancing the protein stability of N-Myc in neuroblastoma. KLHL37 directly interacted with N-Myc to disrupt N-Myc-FBXW7 interaction, thereby stabilizing N-Myc and enabling tumor progression. Suppressing KLHL37 effectively induced the degradation of N-Myc and had a profound inhibitory effect on the growth of MYCN-amplified neuroblastoma. Notably, we identified RTA-408 as an inhibitor of KLHL37 to disrupt the KLHL37-N-Myc complex, promoting the degradation of N-Myc and suppressing neuroblastoma in vivo and in vitro. Moreover, we elucidated the therapeutic potential of RTA-408 for neuroblastoma using patient-derived neuroblastoma cell and patient-derived xenograft tumor models. RTA408's antitumor effects may not occur exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in patients with MYCN-amplified tumors.
N-Myc基因MYCN扩增是神经母细胞瘤中最常见的基因畸变，强烈预示着侵袭性进展和不良临床预后。然而，直接靶向N-Myc活性的临床有效疗法有限。N-Myc是一种转录因子，其稳定性受泛素化依赖性蛋白酶体降解的严格控制。在此，我们发现kelch样蛋白37（KLHL37）在增强神经母细胞瘤中N-Myc的蛋白质稳定性方面发挥了关键作用。KLHL37直接与N-Myc相互作用，破坏N-Myc与FBXW7的相互作用，从而稳定N-Myc并促进肿瘤进展。抑制KLHL37可有效诱导N-Myc降解，对MYCN扩增的神经母细胞瘤生长具有深远的抑制作用。值得注意的是，我们鉴定出RTA-408是KLHL37的抑制剂，可破坏KLHL37-N-Myc复合物，促进N-Myc降解，并在体内和体外抑制神经母细胞瘤。此外，我们使用患者来源的神经母细胞瘤细胞和患者来源的异种移植肿瘤模型阐明了RTA-408对神经母细胞瘤的治疗潜力。RTA408的抗肿瘤作用可能并非仅通过KLHL37产生，未来有望开发出特异性的KLHL37抑制剂。这些发现不仅揭示了KLHL37在调节N-Myc稳定性方面的生物学功能，还表明抑制KLHL37是一种有前景的神经母细胞瘤治疗方案，尤其是对于MYCN扩增肿瘤的患者。
