# OTUD4 deubiquitination stabilizes EGFR and activates the PI3K/AKT pathway to promote the invasiveness of triple-negative breast cancer

## TL;DR

This study shows that OTUD4 promotes the spread of triple-negative breast cancer by stabilizing EGFR and activating the PI3K/AKT pathway.

## Contribution

The novel finding is that OTUD4 stabilizes EGFR through direct interaction and ubiquitin cleavage, promoting TNBC invasiveness.

## Key findings

- OTUD4 is overexpressed in triple-negative breast cancer and correlates with poor prognosis.
- OTUD4 stabilizes EGFR by cleaving K48-linked ubiquitin chains and through direct interaction with EGFR.
- OTUD4 is recruited by NRP1 to further stabilize EGFR, promoting cancer progression.

## Abstract

The deubiquitinating enzyme OTUD4 functions as an oncogene in various cancers, but its role in triple-negative breast cancer (TNBC) remains unclear. Through bioinformatics analysis and experimental validation, we demonstrate that OTUD4 is overexpressed in TNBC and correlates with poor prognosis. OTUD4 downregulation reduces TNBC invasiveness, highlighting its oncogenic role. Mechanistically, OTUD4 promotes TNBC progression by stabilizing EGFR expression and activating the PI3K/AKT pathway. This stabilization occurs through two mechanisms: direct interaction between OTUD4 (568–1114aa) and EGFR (958-1210aa) and OTUD4-mediated cleavage of K48-linked polyubiquitin chains. Additionally, OTUD4 is recruited by NRP1 to deubiquitinate and further stabilize EGFR. These findings enhance our understanding of EGFR signaling in TNBC and may inform novel therapeutic strategies.