2. Academic Validation
  3. Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance

  • Mol Cancer. 2024 Apr 29;23(1):86. doi: 10.1186/s12943-024-01996-y.
Jianfeng Cui # 1 2,  Xiaochen Liu # 2 3,  Qinghong Shang 4,  Shuna Sun 5,  Shouzhen Chen 1,  Jianping Dong 6,  Yaofeng Zhu 1,  Lei Liu 1,  Yangyang Xia 1,  Yong Wang 1,  Lu Xiang 2,  Bowen Fan 2,  Jiafeng Zhan 2,  Yadi Zhou 2,  Pengxiang Chen 7,  Renchang Zhao 8,  Xiaofei Liu 9,  Nianzeng Xing 10,  Dalei Wu 11,  Benkang Shi 12,  Yongxin Zou 13
Affiliations

Affiliations

  • 1 Department of Urology, Qilu Hospital, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China.
  • 2 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
  • 3 Department of Clinical laboratory, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
  • 4 Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China.
  • 5 Department of Dermatology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong Provincial Hospital of Traditional Chinese Medicine, Jinan, Shandong, 250011, China.
  • 6 Department of Urology, Shouguang People's Hospital, Weifang, Shandong, 262750, China.
  • 7 Department of Radiation Oncology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
  • 8 Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
  • 9 Departement of Breast and Thyroid Surgery, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong Provincial Hospital of Traditional Chinese Medicine, Jinan, Shandong, 250011, China.
  • 10 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. xingnianzeng@126.com.
  • 11 Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China. dlwu@sdu.edu.cn.
  • 12 Department of Urology, Qilu Hospital, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China. bkang68@sdu.edu.cn.
  • 13 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China. zouyongxin@sdu.edu.cn.
  • # Contributed equally.
PMID: 38685067 DOI: 10.1186/s12943-024-01996-y
Abstract

Background: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated.

Methods: The proteome-wide Deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6.

Results: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder Cancer.

Conclusions: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for Cancer treatment.

Keywords

CDC6; Deubiquitinating enzyme; OTUD6A; Tumorigenesis.

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