2. Academic Validation
  3. ZDHHC9-mediated KLF5 palmitoylation enhances the cAMP/PKA/CREB axis to promote colorectal cancer progression

ZDHHC9-mediated KLF5 palmitoylation enhances the cAMP/PKA/CREB axis to promote colorectal cancer progression

  • Oncogene. 2026 Apr;45(15):1370-1385. doi: 10.1038/s41388-026-03724-w.
Hao Zhang # 1,  Yuan Tian # 1,  Zeyu Xiang # 1,  Feng Han # 2,  Miaomiao Chen # 3,  Chunhui Jiang 1,  Ye Liu 1,  Hanbing Xue 4,  Lipeng Hu 5,  Chunjie Xu 6,  Lei Gu 7,  Qing Xu 8
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
  • 2 Department of Oncology, Lianyungang Oriental Hospital, Lianyungang, 222042, Jiangsu Province, China.
  • 3 Department of Radiology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200040, China.
  • 4 Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 5 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 6 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. [email protected].
  • 7 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. [email protected].
  • 8 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. [email protected].
  • # Contributed equally.
PMID: 41882103 DOI: 10.1038/s41388-026-03724-w
Abstract

S-palmitoylation, a reversible lipid-based post-translational modification, is notably elevated in colorectal Cancer (CRC) due to common lipid metabolism disorders. It has been reported to play crucial roles in regulating membrane composition, cell proliferation, and metastasis in various malignancies such as pancreatic and breast cancers. However, its role in the progression of CRC remains poorly understood. ZDHHC9, a member of the palmitoyl transferase family, is significantly upregulated in CRC patients and correlates with poor prognosis. Knockdown of ZDHHC9 impairs CRC cell proliferation and migration both in vitro and in vivo. RNA Sequencing revealed that ZDHHC9 depletion markedly downregulates the cAMP signaling pathway. Mechanistically, ZDHHC9 knockdown impairs ADCY4 activity by reducing S-palmitoylation of KLF5 at cysteine 438, thereby modulating the ZDHHC9/KLF5/ADCY4 axis and downstream cAMP/PKA/CREB signaling to influence CRC cell proliferation and migration. Our findings demonstrate that ZDHHC9 promotes CRC progression by regulating intracellular cAMP levels through KLF5 palmitoylation, providing a novel therapeutic perspective targeting palmitoylation in CRC. The mechanism diagram of this study. ZDHHC9 mediates palmitoylation of KLF5 at cysteine 438, thereby enhancing ADCY4 activity and increasing intracellular cAMP levels. This elevation in cAMP promotes PKA and phosphorylation of CREB, ultimately activating the cAMP/PKA/CREB signaling pathway, which contributes to the regulation of CRC cell proliferation, migration, and resistance to 5-FU. (Created with BioRender.com).

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