# Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression

## TL;DR

This study shows that USP8 and the Hippo/YAP axis work together in a feedback loop to promote the progression of triple-negative breast cancer.

## Contribution

The discovery of a positive feedback loop between USP8 and the Hippo/YAP axis in TNBC provides new insights into cancer progression mechanisms.

## Key findings

- USP8 stabilizes YAP by suppressing its K48-linked polyubiquitination.
- YAP enhances USP8 transcription by binding to its promoter region.
- USP8 inhibition reduces TNBC progression and correlates with poor patient survival.

## Abstract

The hyper-activation of the Hippo/YAP axis was observed in triple-negative breast cancer (TNBC), which was crucial for tumor progression. The over-activation of YAP in TNBC remains unexplained, despite the continued functionality of the inhibitory phospho-cascade. Recently, studies revealed that the ubiquitin modifications of YAP also play important roles in the Hippo/YAP axis and cancer progression. In order to understand the potential mechanisms of ubiquitination and deubiquitination process in YAP function, we carried out siRNA screening for critical deubiquitinases in TNBC. Via the deubiquitinases (DUB) library, we identified Ubiquitin Specific Peptidase 8 (USP8) as an important effector in YAP function and TNBC progression. Inhibition of USP8 hampered TNBC progression via Hippo signaling. Clinical data revealed that USP8 expression correlated with YAP protein level and poor survival in TNBC patients. Biochemical evaluations revealed that USP8 has the ability to connect with YAP and suppress K48-linked polyubiquitination, thereby enhancing the stability of YAP. Interestingly, YAP directly binds to the USP8 promoter region, enhancing its transcription in TNBC. Our study revealed a forward feedback loop between USP8 and Hippo signaling in TNBC, indicating USP8 as a potential therapeutic drug targets in TNBC.