USP7 protects histone H1.2 from proteasome-mediated degradation to facilitate DNA repair and pancreatic neuroendocrine neoplasms progression

Ubiquitin-specific protease 7 (USP7), a deubiquitinase, is involved in tumor progression. However, its roles in pancreatic neuroendocrine neoplasms (pNENs) remain unclear. The main objective of this study was therefore to investigate the molecular mechanism of how USP7 promoted pNEN progression. Proteomics and ubiquitin-omics were used to identify the substrates for USP7. We investigated the roles of USP7 and histone H1.2 in DNA repair in pNEN cells using comet assays and γ-H2AX immunofluorescence. The synergistic effects of cisplatin and the USP7 inhibitor, P005091, were evaluated using CCK-8, colony formation, and EdU assays. Western blot analysis was conducted to characterize the PI3K/AKT/mTOR signaling pathway. In vivo, the efficacy of the combination therapy was tested in xenograft models. The results showed a significant increase in USP7 levels in the tissues and cells of pNENs. Furthermore, USP7 was found to promote the proliferation, migration, and invasion of pNENs both in vitro and in vivo. Mechanistically, USP7 facilitated DNA repair through its interaction with histone H1.2 and the activation of the PI3K/AKT/mTOR pathway. The combination of cisplatin and P005091, a USP7 inhibitor, synergistically inhibited tumor growth and DNA repair in both in vitro and in vivo models, without exhibiting significant toxicity. In conclusion, USP7 was a key regulator of DNA repair in pNENs. The combination of cisplatin and P005091 therefore holds promise as a therapeutic strategy for pNENs.