UCHL1 deubiquitinates CIP2A to promote tumor progression in gastric cancer

Gastric cancer is one of the most prevalent malignancies worldwide and the fourth leading cause of cancer-related mortality. The intracellular protein degradation mechanisms, both Ubiquitination and Deubiquitination are called proteostasis, which regulate protein stability and play essential roles in tumorigenesis. Among deubiquitinases, UCHL1 has been implicated in the progression of numerous types of cancers, but its functional role in gastric cancer remains to be fully understood. In this study, we found that UCHL1 expression is markedly upregulated in gastric cancer tissues compared to adjacent normal tissues. Also, elevated UCHL1 expression is associated with poor patient's prognosis, supporting its potential role as an oncogenic factor and knockdown of UCHL1 suppressed cell proliferation, migration and invasion in gastric cancer cells. We sought to identify novel binding partners of UCHL1 and revealed that CIP2A is a substrate of UCHL1. Furthermore, UCHL1 downregulation led to reduced expression of the c-Myc protein, a downstream target of CIP2A, followed by suppression of the cell cycle, particularly through the regulation of Cyclin D1. These findings demonstrate that UCHL1 promotes cell growth via the CIP2A-c-Myc-Cyclin D1 axis, underscoring its potential as a therapeutic target in gastric cancer.