Poly(ADP-Ribose) Glycohydrolase Enforces p21 Degradation via dePARylation to Promote Gastric Cancer Progression

Authors

Yangchan Hu
Qimei Bao
Yixing Huang
Yan Wang
Xin Zhao
Junjun Nan
Yuxin Meng
Mingcong Deng
Yuancong Li
Zirui Zhuang
Hanyi He
Dan Zu
Yuke Zhong
Chunkai Zhang
Bing Wang
Ran Li
Yanhua He
Qihan Wang
Min Liu
John A Tainer
Yin Shi
Xiangdong Cheng
Ji Jing
Zu Ye

Language

English

Publication Date

3-2-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI195538

PMID

41538291

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

Humans, Stomach Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Ubiquitination, Glycoside Hydrolases, Cell Line, Tumor, Proteolysis, Neoplasm Proteins, Mice, Animals, Disease Progression, Female, Male, Ubiquitin-Protein Ligases, Cell biology, Drug screens, Gastric cancer, Gastroenterology, Oncology, Ubiquitin-proteosome system

Published Open-Access

yes

Recommended Citation

Hu, Yangchan; Bao, Qimei; Huang, Yixing; et al., "Poly(ADP-Ribose) Glycohydrolase Enforces p21 Degradation via dePARylation to Promote Gastric Cancer Progression" (2026). Faculty, Staff and Student Publications. 6576.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6576