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.
Shuyu Zhao,Nan Lv,Tianyi Liu,Yuhong Sun,Peiling Li
Preeclampsia (PE), a rare complication with a high incidence and mortality rate, causes tremendous mental and physical impairment to pregnant women. Emerging studies have identified that PE was primarily induced by inadequate trophoblast migration and invasion. Poly(A) Binding Protein Cytoplasmic 1 (PABPC1) is a critical modulator of mRNA translation and stability, with established role in modulating proliferation, apoptosis, and invasion of tumor cells. Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4), which negatively regulates apoptosis, is downregulated in placental tissues of patients with early-onset preeclampsia (EOPE). Notably, 3'UTR motif of TMBIM4 mRNA contains PABPC1 binding site. Here, we investigated the functional role of PABPC1 on regulating proliferation and invasion of trophoblast cells, and how PABPC1 modulated mRNA stability of TMBIM4. HTR-8/SVneo cells transfected with silencing or overexpressed PABPC1 plasmid were applied as the in vitro model. The results revealed that PABPC1 facilitated cell proliferation, migration, and invasion as well as inhibited apoptosis. Moreover, Sprague Dawley rats were received intraperitoneal lipopolysaccharides administration at 40 μg/kg on gestational days 14.5, 15.5, and 16.5. Upregulated PABPC1 ameliorated elevated blood pressure and severe kidney impairment. Furthermore, for the rescue experiments, the effect of PABPC1 on boosting cell proliferation and invasion was blocked by silencing TMBIM4. More interestingly, according to RIP-qPCR and dual luciferase reporter assays, PABPC1 enhanced TMBIM4 expression through enhancing its mRNA stability via binding to its 3'UTR. Taken together, PABPC1 suppressed EOPE development through boosting trophoblast proliferation and invasion by elevating TMBIM4 mRNA stability. Our findings firstly elucidated the vital effect of PABPC1 on EOPE pathogenesis and highlighted that PABPC1 upregulation might be developed as a promising strategy for EOPE treatment.
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