Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma

Tian-Jiao Li; Kai-Zhou Jin; Hong-Yu Zhou; Zhen-Yu Liao; Hui-Ru Zhang; Sai-Meng Shi; Meng-Xiong Lin; Shou-Jie Chai; Qing-Lin Fei; Long-Yun Ye; Xian-Jun Yu; Wei-Ding Wu

doi:10.1016/j.canlet.2023.216411

Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma

Cancer Lett. 2023 Nov 1:576:216411. doi: 10.1016/j.canlet.2023.216411. Epub 2023 Sep 26.

Authors

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
² Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong,Hong Kong, China.
³ Department of Oncology, Ningbo First Hospital, Ningbo, China.
⁴ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yelongyun@fudanpci.org.
⁵ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
⁶ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: wuweiding@fudanpci.org.

PMID: 37757903
DOI: 10.1016/j.canlet.2023.216411

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.

Keywords: CLK2; Deubiquitination; PABPC1; Pancreatic cancer; USP10.