# UCHL1 Promotes Gastric Cancer Progression by Regulating CIP2A Degradation

## TL;DR

This study shows that UCHL1, a deubiquitinating enzyme, promotes gastric cancer by stabilizing CIP2A and enhancing c-Myc signaling, leading to poor patient outcomes.

## Contribution

The study identifies UCHL1 as a novel oncogenic driver in gastric cancer through its regulation of CIP2A and c-Myc signaling.

## Key findings

- UCHL1 is upregulated in gastric cancer tissues and linked to poor prognosis.
- UCHL1 knockdown reduces CIP2A levels, c-Myc signaling, and cell proliferation in gastric cancer cells.
- UCHL1 inhibition arrests the cell cycle in the G1 phase by downregulating cyclin D1.

## Abstract

Background: Gastric cancer is one of the most prevalent malignancies worldwide and the fourth leading cause of cancer-related mortality. Protein ubiquitination and deubiquitination regulate protein stability as post-translational modifications, playing essential roles in tumorigenesis. Although UCHL1, a deubiquitinating enzyme (DUB), is implicated in the progression of several cancer types, its role in gastric cancer remains unclear. Methods: Kaplan–Meier analysis and gastric cancer patient tissues were used to assess UCHL1 expression. Cell viability assay, colony-forming assay, and transwell migration and invasion assay were performed to evaluate cell growth. Immunoprecipitation and Western blotting analyzed protein expression and interactions. Results: This study demonstrates that UCHL1 expression is markedly upregulated in gastric cancer tissues compared to normal tissues. Elevated UCHL1 expression is associated with poor patient prognosis, supporting its potential role as an oncogenic factor. Reduced UCHL1 expression suppressed cell proliferation, migration, and invasion in gastric cancer cell lines. As the underlying mechanism, we identified CIP2A, a known oncogenic regulator of c-Myc, as a downstream effector of UCHL1. UCHL1 knockdown reduced CIP2A protein levels via deubiquitination, attenuated c-Myc signaling, and decreased expression of key cell cycle regulators. Furthermore, UCHL1 knockdown significantly downregulated cyclin D1 expression, arresting the cell cycle in the G1 phase and inhibiting cell proliferation. Conclusions: Collectively, our findings reveal that UCHL1 promotes gastric cancer progression, highlighting it as a potential therapeutic target.