Mechanistic and Functional Characterization of ABTB2 as a Novel Target for Pancreatic Cancer Therapy
Language
English
Publication Date
12-18-2025
Journal
Molecular Therapy Oncology
DOI
10.1016/j.omton.2025.201080
PMID
41322190
PMCID
PMC12664368
PubMedCentral® Posted Date
11-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
BTB/POZ domain-containing proteins are increasingly recognized for their context-dependent roles in cancer, acting as either tumor suppressors or oncogenic drivers depending on the cancer type. Among them, the function of ankyrin repeat and BTB domain-containing protein 2 (ABTB2) in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, has remained unexplored. In this study, we employed comprehensive functional genomics approaches—siRNA/shRNA knockdown, CRISPR-Cas9 knockout, plasmid-based overexpression, and a Cre-LoxP transgenic mouse model—to systemically modulate ABTB2 expression in human and murine PDAC cell lines, as well as in the KPC mouse model of PDAC. Our gain- and loss-of-function studies revealed that ABTB2 plays a pivotal tumor-suppressive role, significantly impairing PDAC cell oncogenicity in vitro and tumorigenesis in vivo. Importantly, therapeutic targeting of ABTB2 using adeno-associated virus serotype 2 (AAV2) and lipid nanoparticles (LNPs) demonstrated marked anti-tumor efficacy and synergized with 5-fluorouracil (5-FU) to enhance treatment outcomes. Transcriptomic analysis, immunoprecipitation, and functional assays demonstrated that ABTB2 interacts with tumour necrosis factor receptor-associated protein 1 (TRAP1), promoting its ubiquitin-dependent degradation and thereby suppressing key oncogenic Wnt/β-catenin and PI3K/Akt signaling pathways. Notably, TRAP1 inhibitors are currently in phase I clinical trials as potential anticancer agents. Our findings provide mechanistic insight and underscore the ABTB2/TRAP1 axis as a promising therapeutic target for PDAC treatment.
Keywords
MT: Regular Issue, pancreatic ductal adenocarcinoma, PDAC, ankyrin repeat and BTB/POZ domain containing protein 2, ABTB2, TNF receptor associated protein 1, TRAP1, Wnt/β-catenin signaling pathway, targeted therapy
Published Open-Access
yes
Recommended Citation
Lyu, Nan; Olaoba, Olamide T; Wang, Qiongling; et al., "Mechanistic and Functional Characterization of ABTB2 as a Novel Target for Pancreatic Cancer Therapy" (2025). Faculty, Staff and Students Publications. 7860.
https://digitalcommons.library.tmc.edu/baylor_docs/7860