α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer.
Theranostics
; 12(3): 1173-1186, 2022.
Article
in En
| MEDLINE
| ID: mdl-35154481
ABSTRACT
Background:
The cytoskeletal linker protein α-Catulin has been shown to be important for tumor progression in various cancers. However, its role in the regulation of cancer stemness remains unclear.Methods:
Phenotypic effects of α-Catulin on the cancer stem cell (CSC)-like properties and metastasis were examined by in vitro sphere formation assay, migration assay, invasion assay, and in vivo xenografted animal models. Yeast two-hybrid assay, co-immunoprecipitation assay, and cycloheximide chase assay were performed to confirm the effect of α-Catulin on the WWP1-mediated degradation of KLF5. CPTAC and TCGA database were analyzed to determine the clinical association of α-Catulin, KLF5, and stemness-associated signatures in lung adenocarcinoma.Results:
We report that α-Catulin increases cancer stem-like properties in non-small cell lung cancer (NSCLC). The expression of α-Catulin is elevated in tumor spheres compared to sphere-derived adherent cells and promotes the acquisition of cancer stemness characteristics in vitro and in vivo. Mechanistically, the interaction of α-Catulin and the C-terminal region of Kruppel-like transcription factor KLF5 results in the inhibition of WWP1-mediated degradation of KLF5. Accordingly, increased protein expression of KLF5 is observed in clinical specimens of lung adenocarcinoma with high expression of α-Catulin compared to specimens with low α-Catulin-expression. Knockdown of KLF5 abrogates α-Catulin-driven cancer stemness. α-Catulin is known to interact with integrin-linked kinase (ILK). Notably, an ILK inhibitor disrupts the α-Catulin-KLF5 interaction, promotes the degradation of KLF5, and decreases α-Catulin-driven cancer stemness. Importantly, we identify a CTNNAL1/ILK/KLF5 three-gene signature for predicting poor overall survival in patients with lung adenocarcinoma.Conclusions:
These findings reveal a molecular basis of α-Catulin-enhanced KLF5 signaling and highlight a role for α-Catulin in promoting cancer stemness.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ubiquitin-Protein Ligases
/
Alpha Catenin
/
Kruppel-Like Transcription Factors
/
Adenocarcinoma of Lung
/
Lung Neoplasms
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Theranostics
Year:
2022
Document type:
Article
Affiliation country:
Taiwán