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USP7 promotes non-small-cell lung cancer cell glycolysis and survival by stabilizing and activating c-Abl.
He, Yuanming; Jiang, Shuoyi; Zhong, Yueya; Wang, Xiaoge; Cui, Yaoli; Liang, Jingpei; Sun, Yuening; Zhu, Zhigang; Huang, Zhenqian; Mao, Xinliang.
Affiliation
  • He Y; Department of Hematology, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
  • Jiang S; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Zhong Y; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Wang X; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Cui Y; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Liang J; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Sun Y; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Zhu Z; Department of Hematology, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
  • Huang Z; Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • Mao X; Division of Hematology & Oncology, Department of Geriatrics, Guangzhou First People's Hospital, College of Medicine, South China University of Technology, Guangzhou, Guangdong, P. R. China.
Clin Transl Med ; 13(12): e1509, 2023 12.
Article in En | MEDLINE | ID: mdl-38082439
ABSTRACT

BACKGROUND:

Abelson tyrosine kinase (c-Abl) is frequently mutated and highly expressed, and promotes non-small-cell lung cancer (NSCLC) survival, metastasis and tumorigenesis. c-Abl could also be modified through ubiquitination, but the underlying mechanism is not well understood.

METHODS:

Mass spectrometry assays were performed to search c-Abl deubiquitination enzymes. The molecular mechanism was determined using Co-IP assays, pull-down assays, Western blotting upon gene knockdown or overexpression. Cell lines and animal models were used to investigate the role of c-Abl and USP7 in NSCLC. EdU staining assay and Transwell assay were performed to evaluate the proliferation and migration ability of NSCLC cells, respectively.

RESULTS:

Ubiquitin-specific protease 7 (USP7) is found to upregulate c-Abl via the deubiquitinase screen. USP7 interacts with c-Abl and decreases its K48-linked polyubiquitination, thereby increasing the stability of c-Abl. In addition to the wild-type one, c-Abl mutants can also be deubiquitinated and stabilized by USP7. Moreover, USP7 promotes c-Abl accumulation in cytoplasm by increasing its binding to 14-3-3α/ß and activates the oncogenic c-Abl signalling pathway. Furthermore, the USP7/c-Abl axis promotes NSCLC cell glycolysis by direct phosphorylating and stabilizing hexokinase-2 (HK2). Knockdown of USP7 or c-Abl suppresses NSCLC cell glycolysis and reduces lactate production. Further studies revealed that overexpression of USP7 facilitates NSCLC cell growth and metastasis as well as xenograft growth in nude mice, while these activities are suppressed with USP7 or c-Abl being knocked down.

CONCLUSIONS:

USP7 is a deubiquitinase of c-Abl and upregulates its oncogenic activity. USP7 promotes NSCLC cell metabolism by activating c-Abl and HK2. Targeting the USP7/c-Abl/HK2 axis might be a potential strategy to the precision therapy of NSCLC.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Lung Neoplasms Limits: Animals / Humans Language: En Journal: Clin Transl Med Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Lung Neoplasms Limits: Animals / Humans Language: En Journal: Clin Transl Med Year: 2023 Document type: Article