结直肠癌 (CRC) 的肿瘤复发和转移是大多数结直肠癌相关死亡的原因。迫切需要深入研究CRC转移的发病机制并寻找新的治疗靶点。本研究旨在探讨泛素特异性肽酶 15 (USP-15) 对 CRC 进展的影响。在体内，建立CRC肿瘤肝转移的小鼠模型以研究USP-15的作用。在体外，通过 Transwell 实验评估 CRC 细胞的迁移和侵袭能力。通过球体形成测定来评估细胞干性。通过免疫共沉淀、双荧光素酶报告基因测定、寡核苷酸下拉测定和染色质免疫沉淀测定进一步探讨了潜在的机制。结果显示，USP-15在CRC肝转移患者和CRC高转移潜能细胞系中表达上调。 USP-15 的缺失会抑制体外 CRC 细胞的上皮间质转化 (EMT)、迁移、侵袭和干细胞特性。 USP-15 的下调可减少小鼠体内的肝转移。 USP-15上调获得了相反的效果。随后，USP-15 使转录因子 AP-4 (TFAP4) 去泛素化并增强其蛋白质稳定性。 TFAP4可以转录激活多梳族环指1（PCGF1）。 USP-15 的促癌作用可以通过敲除 TFAP4 或 PCGF1 来恢复。结论：USP-15 通过增强 CRC 中的细胞干性和 EMT 来促进肝转移，这至少部分是由 PCGF1 上调后 TFAP4 去泛素化介导的。版权所有 © 2024。由 Elsevier Inc. 出版。

The tumor recurrence and metastasis of colorectal cancer (CRC) are responsible for most of CRC-linked mortalities. It is an urgent need to deeply investigate the pathogenesis of CRC metastasis and look for novel targets for its treatment. The current study aimed to investigate the effects of ubiquitin-specific peptidase 15 (USP-15) on the CRC progression. In vivo, a mouse model of liver metastasis of CRC tumor was established to investigate the role of USP-15. In vitro, the migrated and invasive abilities of CRC cells were assessed by transwell assay. Cell stemness was evaluated by using sphere formation assay. The underlying mechanism was further explored by employing the co-immunoprecipitation, dual luciferase reporter assay, oligonucleotide pull-down assay, and chromatin immunoprecipitation assay. The results showed that USP-15 was upregulated in CRC patients with liver metastasis and high metastatic potential cell lines of CRC. Loss of USP-15 repressed the epithelial-to-mesenchymal transition (EMT), migration, invasion, and stemness properties of CRC cells in vitro. Downregulation of USP-15 reduced the liver metastasis of mice in vivo. USP-15 upregulation obtained the contrary effects. Subsequently, USP-15 deubiquitinated transcription factor AP-4 (TFAP4) and enhanced its protein stability. TFAP4 could transcriptionally activated polycomb group ring finger 1 (PCGF1). The pro-cancer effects of USP-15 were rescue by the knockdown of TFAP4 or PCGF1. In conclusions: USP-15 facilitated the liver metastasis by the enhancement of cell stemness and EMT in CRC, which was at least partly mediated by the deubiquitination of TFAP4 upon the upregulation of PCGF1.Copyright © 2024. Published by Elsevier Inc.