Work

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

Year: 2025

Type: article

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.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.148692