α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer

Chia-Hao Tung; Meng-Fan Huang; Chen-Hsien Liang; Yi-Ying Wu; Jia-En Wu; Cheng-Lung Hsu; Yuh-Ling Chen; Tse-Ming Hong

doi:10.7150/thno.63627

α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer

Theranostics. 2022 Jan 1;12(3):1173-1186. doi: 10.7150/thno.63627. eCollection 2022.

Authors

Chia-Hao Tung¹, Meng-Fan Huang¹, Chen-Hsien Liang², Yi-Ying Wu³, Jia-En Wu¹, Cheng-Lung Hsu⁴, Yuh-Ling Chen^{2

5}, Tse-Ming Hong^{1

3}

Affiliations

¹ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
⁵ Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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.

Keywords: KLF5; WWP1; cancer stem cell; non-small cell lung cancer.; α-Catulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / metabolism
Adenocarcinoma of Lung* / pathology
Cell Line, Tumor
Cell Proliferation
Humans
Kruppel-Like Transcription Factors* / genetics
Kruppel-Like Transcription Factors* / metabolism
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Ubiquitin-Protein Ligases* / metabolism
alpha Catenin* / genetics
alpha Catenin* / metabolism

Substances

CTNNAL1 protein, human
KLF5 protein, human
Kruppel-Like Transcription Factors
alpha Catenin
WWP1 protein, human
Ubiquitin-Protein Ligases