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Theranostics 2022; 12(3):1173-1186. doi:10.7150/thno.63627 This issue Cite

Research Paper

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

Chia-Hao Tung1, Meng-Fan Huang1, Chen-Hsien Liang2, Yi-Ying Wu3, Jia-En Wu1, Cheng-Lung Hsu4, Yuh-Ling Chen2,5✉, Tse-Ming Hong1,3✉

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.

✉ Corresponding authors: Tse-Ming Hong, PhD, Institute of Clinical Medicine, National Cheng Kung University, No. 1, University Road, Tainan 70101, Taiwan; Email: tmhongedu.tw; Phone: 886-6-2353535-4259; Fax: 886-6-2758-781; Yuh-Ling Chen, PhD, E More

Citation:
Tung CH, Huang MF, Liang CH, Wu YY, Wu JE, Hsu CL, Chen YL, Hong TM. α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics 2022; 12(3):1173-1186. doi:10.7150/thno.63627. https://www.thno.org/v12p1173.htm
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Abstract

Graphic 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: α-Catulin, cancer stem cell, KLF5, WWP1, non-small cell lung cancer.

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APA
Tung, C.H., Huang, M.F., Liang, C.H., Wu, Y.Y., Wu, J.E., Hsu, C.L., Chen, Y.L., Hong, T.M. (2022). α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics, 12(3), 1173-1186. https://doi.org/10.7150/thno.63627.

ACS
Tung, C.H.; Huang, M.F.; Liang, C.H.; Wu, Y.Y.; Wu, J.E.; Hsu, C.L.; Chen, Y.L.; Hong, T.M. α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics 2022, 12 (3), 1173-1186. DOI: 10.7150/thno.63627.

NLM
Tung CH, Huang MF, Liang CH, Wu YY, Wu JE, Hsu CL, Chen YL, Hong TM. α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics 2022; 12(3):1173-1186. doi:10.7150/thno.63627. https://www.thno.org/v12p1173.htm

CSE
Tung CH, Huang MF, Liang CH, Wu YY, Wu JE, Hsu CL, Chen YL, Hong TM. 2022. α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics. 12(3):1173-1186.

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