FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth

• Published in: Cell death & disease 2019-06, Vol.10 (7), p.486-11, Article 486
• Main Authors: Zhu, Xiao-Na, He, Ping, Zhang, Liang, Yang, Shuo, Zhang, Hui-Lin, Zhu, Di, Liu, Meng-Di, Yu, Yun
• Format: Article
• Language: English
• Subjects: 13; 13/51; 13/95; 631/67; 631/67/1612/1350; 64; 64/60; 82; 82/29; 82/80; 82/83; A549 Cells; Adenocarcinoma; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Biology; Cell Culture; Cell growth; Cell Line, Tumor; Cell Proliferation - genetics; Cell Proliferation - physiology; Colony-Forming Units Assay; Energy metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; Female; HEK293 Cells; HeLa Cells; Hepatocytes; Humans; Immunoblotting; Immunohistochemistry; Immunology; Immunoprecipitation; Kinases; Life Sciences; Liver cancer; LKB1 protein; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Malignancy; Mice; Mice, Nude; Non-small cell lung carcinoma; Overexpression; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; Therapeutic applications; TOR protein; Ubiquitination - genetics; Ubiquitination - physiology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1732-9

Liver kinase B1 (LKB1) regulates both cell growth and energy metabolism. Inactivated mutations of LKB1, observed in 20–30% of nonsmall cell lung cancers (NSCLC), contribute significantly to lung cancer malignancy progression. However, the upstream signalings regulating LKB1 activity remain incompletely understood. Here, we present evidence that FBXO22 interacts with and promotes polyubiquitination of LKB1. More intriguingly, FBXO22 mediates Lys-63-linked LKB1 polyubiquitination and inhibits kinase activity of LKB1. Furthermore, over-expression of FBXO22 promotes NSCLC cell growth through inhibiting LKB1-AMPK-mTOR signaling in vitro and in vivo. Clinically, FBXO22 is highly expressed in human lung adenocarcinoma and high FBXO22 expression predicts significant poor prognosis. Our study provides new insights into the upstream regulation of LKB1 activation and identifies FBXO22 as a potential therapeutic target for lung cancer treatment.