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  3. Ubiquitin-specific protease 54 regulates GLUT1-mediated aerobic glycolysis to inhibit lung adenocarcinoma progression by modifying p53 degradation

Ubiquitin-specific protease 54 regulates GLUT1-mediated aerobic glycolysis to inhibit lung adenocarcinoma progression by modifying p53 degradation

  • Oncogene. 2024 May 14. doi: 10.1038/s41388-024-03047-8.
Leifeng Chen # 1 2 3 4,  Lin Zhang # 5 6,  Haihua He 1 2 3,  Fei Shao 3,  Zhentao Yu 5,  Yibo Gao 7 8 9 10,  Jie He 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 2 Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 3 Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 4 Medical Center for Cardiovascular Diseases, Neurological Diseases and Tumors of Jiangxi Province, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 5 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.
  • 6 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 7 Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China. gaoyibo@cicams.ac.cn.
  • 8 Laboratory of Thoracic Oncology & Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. gaoyibo@cicams.ac.cn.
  • 9 Translational Medicine Platform, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. gaoyibo@cicams.ac.cn.
  • 10 State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. gaoyibo@cicams.ac.cn.
  • 11 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. hejie@cicams.ac.cn.
  • 12 Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. hejie@cicams.ac.cn.
  • 13 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China. hejie@cicams.ac.cn.
  • 14 State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. hejie@cicams.ac.cn.
  • # Contributed equally.
PMID: 38744954 DOI: 10.1038/s41388-024-03047-8
Abstract

Lung adenocarcinoma (LUAD) is one of the most prevalent types of Cancer. Ubiquitination is crucial in modulating cell proliferation and aerobic glycolysis in Cancer. The frequency of TP53 mutations in LUAD is approximately 50%. Currently, therapeutic targets for wild-type (WT) p53-expressing LUAD are limited. In the present study, we systemically explored the expression of Ubiquitin-Specific Protease genes using public datasets. Then, we focused on Ubiquitin-Specific Protease 54 (USP54), and explored its prognostic significance in LUAD patients using public datasets, analyses, and an independent cohort from our center. We found that the expression of USP54 was lower in LUAD tissues compared with that in the paracancerous tissues. Low USP54 expression levels were linked to a malignant phenotype and worse survival in patients with LUAD. The results of functional experiments revealed that up-regulation of USP54 suppressed LUAD cell proliferation in vivo and in vitro. USP54 directly interacted with p53 protein and the levels of ubiquitinated p53 were inversely related to USP54 levels, consistent with a role of USP54 in deubiquitinating p53 in p53-WT LUAD cells. Moreover, up-regulation of the USP54 expression inhibited aerobic glycolysis in LUAD cells. Importantly, we confirmed that USP54 inhibited aerobic glycolysis and the growth of tumor cells by a p53-mediated decrease in glucose transporter 1 (GLUT1) expression in p53-WT LUAD cells. Altogether, we determined a novel mechanism of survival in the p53-WT LUAD cells to endure the malnourished tumor microenvironment and provided insights into the role of USP54 in the adaptation of p53-WT LUAD cells to metabolic stress.

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