DTL promotes pancreatic cancer progression through ubiquitin-mediated degradation of SMAD4

  • Int J Biol Macromol. 2025 Dec;333(Pt 2):148692. doi: 10.1016/j.ijbiomac.2025.148692.
Xi-Zhuang Pan  1 ,  Ke Tang  2 ,  Li-Kun Ren  3 ,  Shao-Jie Chen  4 ,  Song Chen  5 ,  Si-Yuan Li  6 ,  Ren-Jie Ni  7 ,  Chang-Hao Zhu  8 ,  Xing Wang  9 ,  Yao-Zhen Pan  10
Affiliations
  • 1. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 2. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China; Surgery, Nanming District People's Hospital of Guiyang City, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 3. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 4. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 5. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 6. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 7. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 8. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China; Hepatobiliary Surgery, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 9. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China; Hepatobiliary Surgery, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
  • 10. School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China; Hepatobiliary Surgery, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China. Electronic address: [email protected].
PMID: 41203163 DOI: 10.1016/j.ijbiomac.2025.148692
Abstract

Pancreatic Cancer, known for its aggressive progression and unfavorable prognosis, necessitates the urgent discovery of novel therapeutic targets. This study identifies DTL as an oncogenic driver by employing transcriptome Sequencing of clinical specimens, bioinformatics analysis, and immunohistochemical validation. The findings reveal its overexpression and prognostic significance in pancreatic Cancer. Functional assays have elucidated the role of DTL in enhancing tumor cell proliferation, migration, invasion, and clonogenicity. In vivo models further corroborated that knockdown of DTL resulted in suppressed tumor growth and metastasis, whereas its overexpression facilitated disease progression. Mechanistically, DTL operates as an E3 ubiquitin Ligase, mediating K48-linked ubiquitination and subsequent proteasomal degradation of SMAD4. This process activates the Wnt/β-catenin pathway, thereby promoting tumorigenesis. These findings identify the DTL-SMAD4-Wnt/β-catenin axis as a pivotal signaling cascade and underscore the potential of DTL as a therapeutic target in the context of pancreatic Cancer.

Keywords
DTL; Pancreatic cancer; SMAD4; Ubiquitination; Wnt/β-catenin signaling pathway.
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