Acyltransferase ZDHHC22 promotes N-Myc transcriptional activation to drive neuroblastoma progression and chemoresistance

MYCN-amplified neuroblastoma is one of the most lethal pediatric malignancies, where aberrant N-Myc-driven transcription promotes tumor progression. As direct targeting of N-Myc has proven challenging, current approaches prioritize understanding and modulating the mechanisms that regulate its activity, which remain poorly understood. Here, we demonstrate a crucial role of S-acylation in the regulation of N-Myc transcriptional activity and identify the acyltransferase ZDHHC22 as a key regulator of this process. Mechanistically, ZDHHC22 catalyzes the S-acylation of N-Myc, which enhances its transcriptional activity by facilitating the recruitment of transcriptional coactivators such as TIP60 and GCN5. Furthermore, N-Myc transcriptionally upregulates ZDHHC22, establishing a positive feedback loop that contributes to chemoresistance in high-risk neuroblastoma. Targeting ZDHHC22 suppresses neuroblastoma cell growth in vitro and in vivo, particularly in refractory patient-derived models. Collectively, our findings not only uncover a new biological function of ZDHHC22 in regulating N-Myc transcriptional activation but also indicate that ZDHHC22 is a promising therapeutic target for N-Myc-driven high-risk neuroblastoma, especially MYCN-amplified patients.

MYCN扩增型神经母细胞瘤（MYCN-amplified neuroblastoma）是致死性最强的儿童恶性肿瘤之一，由异常N-Myc驱动的转录过程会促进肿瘤进展。鉴于直接靶向N-Myc已被证实存在技术难点，当前研究优先致力于解析并调控其活性的相关机制，但这类机制目前仍未得到充分阐释。本研究证实了S-酰化（S-acylation）在调控N-Myc转录活性中发挥关键作用，并鉴定出酰基转移酶ZDHHC22为该过程的核心调控因子。从分子机制层面而言，ZDHHC22可催化N-Myc的S-酰化修饰，通过促进转录共激活因子（如TIP60与GCN5）的招募，增强其转录活性。此外，N-Myc可通过转录调控上调ZDHHC22的表达，由此形成正反馈环路，进而参与高危神经母细胞瘤的化疗耐药进程。靶向抑制ZDHHC22可在体外及体内实验中抑制神经母细胞瘤细胞的增殖，在难治性患者来源的肿瘤模型中这一抑制效应尤为显著。综上，本研究不仅揭示了ZDHHC22调控N-Myc转录激活的全新生物学功能，同时也证实ZDHHC22是治疗N-Myc介导的高危神经母细胞瘤（尤其是MYCN扩增型患者）的极具潜力的治疗靶点。