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ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression

Author

Listed:
  • Huan Zhang

    (Huazhong University of Science and Technology)

  • Yan Sun

    (Huazhong University of Science and Technology)

  • Zhaokai Wang

    (Huazhong University of Science and Technology)

  • Xiaoju Huang

    (Huazhong University of Science and Technology)

  • Lu Tang

    (Huazhong University of Science and Technology)

  • Ke Jiang

    (Huazhong University of Science and Technology)

  • Xin Jin

    (Central South University
    Uro-Oncology Institute of Central South University)

Abstract

Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20–YTHDF3–MYC signaling axis in pancreatic cancer.

Suggested Citation

  • Huan Zhang & Yan Sun & Zhaokai Wang & Xiaoju Huang & Lu Tang & Ke Jiang & Xin Jin, 2024. "ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49105-3
    DOI: 10.1038/s41467-024-49105-3
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    References listed on IDEAS

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    1. Zhenxing Zhang & Xin Li & Fan Yang & Chao Chen & Ping Liu & Yi Ren & Pengkai Sun & Zixiong Wang & Yongping You & Yi-Xin Zeng & Xinjian Li, 2021. "DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Isidoro Cobo & Sumit Paliwal & Cristina Bodas & Irene Felipe & Júlia Melià-Alomà & Ariadna Torres & Jaime Martínez-Villarreal & Marina Malumbres & Fernando García & Irene Millán & Natalia Pozo & Joo-C, 2023. "NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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