USP1 promotes cholangiocarcinoma progression by deubiquitinating PARP1 to prevent its proteasomal degradation.

Abstract

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin chain at K197 of PARP1 to prevent its proteasomal degradation, with the consequent PARP1 stabilization being necessary and sufficient to promote the growth and metastasis of CCA in vitro and in vivo. Additionally, we identified the acetyltransferase GCN5 as acetylating USP1 at K130, enhancing the affinity between USP1 and PARP1 and further increasing PARP1 protein stabilization. Finally, both USP1 and PARP1 are significantly associated with poor survival in CCA patients. These findings describe PARP1 as a novel deubiquitination target of USP1 and a potential therapeutic target for CCA.

• Authors: Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 10 Pg. 669 (10 11 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 37821462 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• Poly (ADP-Ribose) Polymerase-1
• Ubiquitin-Specific Proteases
• PARP1 protein, human
• USP1 protein, human

Topics

• Humans
• Poly (ADP-Ribose) Polymerase-1 (genetics)
• Ubiquitin-Specific Proteases (metabolism)
• Cholangiocarcinoma (genetics)