2. Academic Validation
  3. Poly(ADP-ribose) glycohydrolase enforces p21 degradation via dePARylation to promote gastric cancer progression

Poly(ADP-ribose) glycohydrolase enforces p21 degradation via dePARylation to promote gastric cancer progression

  • J Clin Invest. 2026 Jan 15;136(5):e195538. doi: 10.1172/JCI195538.
Yangchan Hu 1 2,  Qimei Bao 1,  Yixing Huang 1 3,  Yan Wang 1 4,  Xin Zhao 1,  Junjun Nan 1 2,  Yuxin Meng 1 2,  Mingcong Deng 1,  Yuancong Li 1 2,  Zirui Zhuang 1 5,  Hanyi He 1,  Dan Zu 1 6,  Yuke Zhong 1,  Chunkai Zhang 1,  Bing Wang 1 2,  Ran Li 1 2,  Yanhua He 1,  Qihan Wang 7,  Min Liu 8,  John A Tainer 8,  Yin Shi 3,  Xiangdong Cheng 1 9 10,  Ji Jing 1 9 10,  Zu Ye 1 9 10 11 12
Affiliations

Affiliations

  • 1 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 2 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
  • 3 Department of Biochemistry and Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China.
  • 4 Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
  • 5 School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (UCAS), Hangzhou, China.
  • 6 School of Life Sciences, Tianjin University, Tianjin, China.
  • 7 College of Biological Sciences, University of California, Davis, California, USA.
  • 8 Departments of Molecular and Cellular Oncology and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 9 Key Laboratory of Prevention, Diagnosis and Therapy of Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China.
  • 10 Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China.
  • 11 Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China.
  • 12 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China.
PMID: 41538291 DOI: 10.1172/JCI195538
Abstract

Dysregulation of cell cycle checkpoints is a Cancer hallmark, with ubiquitination-controlled protein stability playing a pivotal role. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric Cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, which disrupts its association with E3 ubiquitin Ligase, thereby reducing K48-linked ubiquitination and leading to p21 protein stabilization. Moreover, we identify lysine residues K161 and K163 as critical sites for PARG-mediated regulation of p21 ubiquitination. Our findings reveal a posttranslational regulatory axis in which PARG governs cell cycle progression by modulating the PARylation-dependent ubiquitination of p21. These results broaden the understanding of p21 regulation in Cancer and highlight PARG as a potential therapeutic target for GC treatment.

Keywords

Cell biology; Drug screens; Gastric cancer; Gastroenterology; Oncology; Ubiquitin-proteosome system.

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