2. Academic Validation
  3. Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication

Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication

  • NPJ Precis Oncol. 2021 Mar 2;5(1):14. doi: 10.1038/s41698-021-00153-8.
Yueshuo Li 1 2 3,  Feng Shi 1 2 3,  Jianmin Hu 1 2 3,  Longlong Xie 1 2 3,  Lin Zhao 1 2 3,  Min Tang 1 2 3,  Xiangjian Luo 1 2 3,  Mao Ye 4,  Hui Zheng 5,  Min Zhou 1 2 3,  Na Liu 1 2 3,  Ann M Bode 6,  Jia Fan 7,  Jian Zhou 7,  Qiang Gao 7,  Shuangjian Qiu 7,  Weizhong Wu 7,  Xin Zhang 8,  Weihua Liao 9,  Ya Cao 10 11 12 13 14 15
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 2 Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.
  • 3 Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China.
  • 4 Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/ Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China.
  • 5 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
  • 6 The Hormel Institute, University of Minnesota, Austin, MN, USA.
  • 7 Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
  • 8 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 9 Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 10 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China. ycao98@vip.sina.com.
  • 11 Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China. ycao98@vip.sina.com.
  • 12 Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China. ycao98@vip.sina.com.
  • 13 Molecular Imaging Research Center of Central South University, Changsha, Hunan, China. ycao98@vip.sina.com.
  • 14 Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha, China. ycao98@vip.sina.com.
  • 15 National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, China. ycao98@vip.sina.com.
PMID: 33654169 DOI: 10.1038/s41698-021-00153-8
Abstract

p18 is a key negative regulator of cell cycle progression and mediates cell cycle arrest at the G1/S phase. Ubiquitination is the prime mechanism in regulating p18 protein abundance. However, so far no post- translational regulator, especially DUBs, has been identified to regulate the protein stability of p18. In this paper, we identified CYLD as a Deubiquitinase of p18, which binds to and removes the K48-linked polyubiquitylation chains conjugated onto p18, thus stabilizing the p18 protein. Loss of CYLD causes the degradation of p18 and induces the G1/S transition. Epstein-Barr virus (EBV), is the human oncovirus etiologically linked to nasopharyngeal carcinoma (NPC). Here we found that EBV drives a replication passive environment by deregulating the CYLD-p18 axis. Functionally, CYLD inhibits cell proliferation and tumorigenesis through p18 in vivo. Restoring CYLD prevents EBV induced viral replication and tumor growth. Collectively, our results identify CYLD directly stabilizes p18 to regulate the cellular G1/S transition. The reconstitution of CYLD-p18 axis could be a promising approach for EBV-positive Cancer therapy.

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