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

  • Mol Cell. 2026 May 21;86(10):1945-1962.e6. doi: 10.1016/j.molcel.2026.04.002.
Aixiao Xu  1 ,  Jianhua Zhang  2 ,  Bing Wu  2 ,  Minghao Xu  1 ,  Tianrui Wang  2 ,  Chen Shao  2 ,  Shaowei Bing  1 ,  Yunpeng Huang  2 ,  Yanru Yao  2 ,  Jinhu Wang  3 ,  Yinbing Tang  3 ,  Ji Cao  4 ,  Bo Yang  5 ,  Xuejing Shao  6 ,  Qiaojun He  7 ,  Meidan Ying  8
Affiliations
  • 1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China.
  • 2. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3. Department of Surgical Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
  • 4. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, China.
  • 5. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China; School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang, China.
  • 6. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China. Electronic address: [email protected].
  • 7. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China; Cancer Center, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 8. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China; School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang, China; Department of Surgical Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Cancer Center, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 42061401 DOI: 10.1016/j.molcel.2026.04.002
Abstract

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 the mechanisms that regulate its activity, which remain poorly understood. Here, we demonstrate a crucial role of S-acylation in regulating N-Myc transcriptional activity and identify the Acyltransferase zinc finger DHHC-type containing 22 (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 coactivators such as TIP60 and GCN5. Furthermore, N-Myc transcriptionally upregulates ZDHHC22, establishing a 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 uncover a biological function of ZDHHC22 in regulating N-Myc transcriptional activation and indicate that ZDHHC22 is a promising therapeutic target for N-Myc-driven high-risk Neuroblastoma, especially in MYCN-amplified patients.

Keywords
N-Myc; S-acylation; ZDHHC22; chemoresistance; neuroblastoma; transcriptional activation.
Products